Substituted fused bicyclic amines as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of CCR3 of formula (Ia) and (Ib): 
                         
or pharmaceutically acceptable salt forms thereof, wherein Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ , R 6 , a, b, c, d, and u are as defined herein. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis using said modulators are disclosed.

This application claims the benefit of U.S. Provisional Application No. 60/545,805, filed Feb. 19, 2004, incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates generally to modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1, -2, and -3) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed “chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”) [MIP-1α, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3 (or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or “CKR-4” or “CC-CKR-4”) [TARC, MIP-1α, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or “CKR-5” OR “CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or “CKR-6” or “CC-CKR-6”) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or “CKR-8” or “CC-CKR-8”) [I-309, TARC, MIP-1β] (Napolitano et al., J. Immunol., 157, 2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); and CCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol., 16, 1249-1256 (1997)).

In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).

Chemokine receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. In addition, agents which modulate chemokine receptors would also be useful in infectious diseases such as by blocking infection of CCR3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.

Small molecules including ureido-substituted cyclic amines, arylalkyl cyclic amines, acyclic diamines, cyclic diamines, 4,4-disubstituted piperidines, 1,2,3,4-tetrahydroisoquinolines, imidazolium compounds, 1,4-disubstituted piperazines, piperidines, bicyclic piperidines, substituted furo [2,3,-B] pyridines, and diazabicyclic compounds have been reported in the literature as antagonists of MCP-1 and/or CCR receptors. For example, Trivedi et al, Ann. Reports Med. Chem. 2000, 35, 191; Shiota et al., WO 99/25686; Shiota et al., WO 00/69815; C. Tarby and W. Moree, WO 00/69820; P. Carter and R. Cherney, WO 02/50019; R. Cherney, WO 02/060859; Matsumoto et al., WO 03/091245; Jiao et al., WO 03/093231; Axten et al., WO 03/101970; Pennell et al., WO 03/105853; Blumberg et al., WO 04/009550; Blumberg et al., WO 04/009588; Toupence et al., WO 04/012671; and Colon-Cruz et al., WO-02/070523. Similarly, MCP-1 and/or CCR receptor antagonistic indolopiperidines quaternary amines, spiropiperidines, 2-substituted indoles and benzimidazoles, pyrazolone derivatives, dialkylhomopiperazines, N,N-dialkylhomopiperazines, bicyclic pyrroles, tetrahydropyranyl cyclopentyl tetrahyropyridopyridines, N-aryl sulfonamides, pyrimidyl sulphone amides, 3,4-diamine-3-cyclobutene-1,2-diones, substituted heterocyclic compounds, substituted benzanilides, bipiperidinyl derivatives, and 5-aryl pentadienamides have been reported in the literature. For example, Forbes et al., Bioorg. Med. Chem. Lett. 2000, 10, 1803; Mirzadegan et al., J. Biol. Chem. 2000, 275, 25562; Baba et al., Proc. Natl. Acad. Sci. 1999, 96, 5698; A. Faull and J. Kettle, WO 00/46196; Barker et al., WO 99/07351; Barker et al., WO 99/07678; Padia et al., U.S. Pat. No. 6,011,052; Connor et al., WO 98/06703; Shiota et al., WO 97/44329; Barker et al., WO 99/40913; Barker et al., WO 99/40914; Jiao et al., WO 03/092568; Fleming et al., WO 03/99773; Habashita et al., WO 04/007472; Ebden et al., WO 04/011443; Taveras et al., WO 04/011418; Bondinell et al., WO 04/010942, WO 04/010943 and WO 04/011427; Albert et al., WO 02/081449; and Carson, et al., Cambridge Health Tech Institute Chemokine Symposium, McLean, Va., USA, 1999.

However, the foregoing reference compounds are readily distinguished structurally from the present invention by virtue of substantial differences in the terminal functionality, the attachment functionality, the core functionality, and/or nature of the bicyclic ring system. Accordingly, the prior art does not disclose nor suggest the unique combination of structural fragments that embody the novel compounds described herein. Furthermore, the prior art does not disclose or suggest that the compounds of the present invention would be effective as MCP-1 antagonists.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel agonists or antagonists of CCR-3, or pharmaceutically acceptable salts or prodrugs thereof.

The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating inflammatory diseases and allergic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides novel substituted fused bicyclic amines, preferably urea-substituted fused bicyclic amines, for use in therapy.

Further, the present invention provides the use of novel substituted fused bicyclic amines, preferably urea-substituted fused bicyclic amines, for the manufacture of a medicament for the treatment of allergic disorders.

These and other aspects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formulas (Ia) and (Ib):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein Z, R¹, R², R³, R⁴, R⁵, R^(5′), R⁶, a, b, c, d, and u are defined below, and are effective modulators of chemokine activity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In one embodiment, the present invention discloses novel compounds of formulas (Ia) and (Ib):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

-   Z is selected from O, S, N(R^(d)), C(CN)₂, CH(NO₂), and CH(CN); -   R¹ and R² are independently selected from H, C₁₋₈ alkyl, C₂₋₈     alkenyl, and C₂₋₈ alkynyl; -   R^(d) is selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,     CON(R^(f))R^(f), OR^(e), CN, NO₂, and (CH₂)_(r)-phenyl substituted     with 0-3 R¹⁸; -   R^(e), at each occurrence, is independently selected from H, C₁₋₆     alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R¹⁸; -   R^(f), at each occurrence, is independently selected from H, C₁₋₆     alkyl, C₃₋₆ cycloaklyl, and phenyl substituted with 0-3 R¹⁸, or     optionally, two R^(f)'s may be taken together with the nitrogen to     which both are attached to form a pyrrolidine, piperidine,     piperazine or morpholine ring; -   R³ is selected from a (CR^(3′)R^(3′))_(r)—C₃₋₁₀ carbocyclic residue     substituted with 0-5 R¹⁵ and a (CR^(3′)R^(3′))_(r)-5-10 membered     heterocyclic system containing 1-4 heteroatoms selected from N, O,     and S, substituted with 0-3 R¹⁵; -   R^(3′), at each occurrence, is independently selected from H, C₁₋₆     alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl; -   R⁴ is absent, taken with the nitrogen to which it is attached to     form an N-oxide, or selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈     alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),     (CH₂)_(q)C(O)NR^(4a)R^(4a), (CH₂)_(q)C(O)OR^(4b), and a     (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4c); -   R^(4a), at each occurrence, is independently selected from H, C₁₋₆     alkyl, (CH₂g)_(r)C₃₋₆ cycloalkyl, and phenyl; -   R^(4b), at each occurrence, is independently selected from C₁₋₆     alkyl, C₂₋₈ alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and     phenyl; -   R^(4c), at each occurrence, is independently selected from C₁₋₆     alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,     CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH,     (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4a)R^(4a), and (CH₂)_(r)phenyl; -   R⁵ is selected from

-   Y is selected from O, N(R²⁵), S, S(O), and S(O)₂; -   ring B is a 5-7 membered cycloalkyl ring optionally containing a     C═O, and being substituted with 0-2 R^(11a), wherein the cycloalkyl     ring is fused with a benzo group substituted with 0-3 R¹⁶ or is     fused with a 5-6 membered aromatic heterocyclic ring having 0-3 N,     0-1 O, or 0-1 S, the heterocyclic ring being substituted with 0-3     R¹⁶; -   alternatively, ring B is a 5-7 membered saturated heterocyclic ring     containing 0-1 O, N(R²⁵), S, S(O), and S(O)₂, substituted with 0-2     R^(11a), wherein the heterocyclic ring is fused with a benzo group     substituted with 0-3 R¹⁶ or is fused with a 5-6 membered aromatic     heterocyclic ring having 0-3 N, 0-1 O, or 0-1 S, the heterocyclic     ring being substituted with 0-3 R¹⁶; -   provided that if ring B is a heterocyclic ring, then the number of     carbon atoms separating the heteroatom of ring B and the nitrogen     atom of formula (Ia) or (Ib) bonded to R⁵ is at least 2; -   R^(5′) is selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,     (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),     (CH₂)_(q)C(O)NR^(4a)R^(4a), (CH₂)_(q)C(O)OR^(4b), and a     (CH₂)_(r)—C₃-10 carbocyclic residue substituted with 0-3 R^(4c); -   alternatively, in formula (Ib), R⁵ and R^(5′) may together form a     saturated ring containing 5 to 7 atoms optionally substituted with     C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,     (CH₂)_(q)C(O)R^(4b), (CH₂)_(q)C(O)NR^(4a)R^(4a),     (CH₂)_(q)C(O)OR^(4b), (CH₂)_(r)—R^(5a), or O—R^(5a); -   R^(5a) is selected from a C₃₋₁₀ carbocyclic residue substituted with     0-5 R¹⁶, and a 5-10 membered heterocyclic residue containing 1-4     heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁶; -   R⁶, at each occurrence, is independently selected from C₁₋₆ alkyl,     C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(t)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃,     CN, (CH₂)_(r)NR^(6a)R^(6a), (CH₂)_(r)OH, (CH₂)_(r)OR^(6b),     (CH₂)_(r)SH, (CH₂)_(r)SR^(6b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(6b),     (CH₂)_(r)C(O)NR^(6a)R^(6a), (CH₂)_(r)NR^(6d)C(O)R^(6a),     (CH₂)_(r)C(O)OR^(6b), (CH₂)_(r)OC(O)R^(6b), (CH₂)_(r)S(O)R^(6b),     (CH₂)_(r)S(O)₂R^(6b), (CH₂)_(S)(O)₂NR^(6a)R^(6a),     (CH₂)_(r)NR^(6d)S(O)₂R^(6b), and (CH₂)_(t)phenyl substituted with     0-3 R^(6c);     with the proviso that if R⁶ is attached to a carbon atom which also     is attached to a nitrogen atom, or if two occurrences of R⁶ are     attached to the same carbon atom, then r contained within the     definition of such R⁶ must be greater than 0; -   R^(6a), at each occurrence, is independently selected from H, C₁₋₆     alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c); -   R^(6b), at each occurrence, is independently selected from C₁₋₆     alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c); -   R^(6c), at each occurrence, is independently selected from C₁₋₆     alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,     (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and     (CH₂)_(r)NR^(6d)R^(6d); -   R^(6d), at each occurrence, is independently selected from H, C₁₋₆     alkyl, and C₃₋₆ cycloalkyl; -   R^(11a) and R^(12a), at each occurrence, are independently selected     from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(t)C₃₋₆     cycloalkyl, (CF₂)_(t)CF₃, (CH₂)_(r)N(R^(18a))R^(18b), (CH₂)_(r)OH,     (CH₂)_(r)OR¹⁹, (CH₂)_(r)SH, (CH₂)_(r)SR¹⁹, (CH₂)_(r)C(O)OH,     (CH₂)_(r)C(O)R¹⁹, (CH₂)_(r)C(O)N(R^(18a))R^(18b),     (CH₂)_(r)N(R^(18c)) C(O) R¹⁹, (CH₂)_(r)C(O)OR¹⁹, (CH₂)_(r)OC(O)R¹⁹,     (CH₂)_(r)S(O)R¹⁹, (CH₂)_(r)S(O)₂R¹⁹,     (CH₂)_(r)S(O)₂N(R^(18a))R^(18b), (CH₂)_(r)N(R^(18c))S(O)₂R¹⁹, and     (CH₂)_(t)phenyl substituted with 0-3 R¹⁸; -   with the proviso that if s is 1, then r contained within the     definition of such R^(11a) and R^(12a) attached to carbon atoms     bonded directly to Y must be greater than 0; -   R^(11b), R^(12b), R^(14a) and R^(14b), at each occurrence, are     independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈     alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃,     (CH₂)_(q)N(R^(18a))R^(18b), (CH₂)_(q)OH, (CH₂)_(q)OR¹⁹, (CH₂)_(q)SH,     (CH₂)_(q)SR¹⁹, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R¹⁹,     (CH₂)_(r)C(O)N(R^(18a))R^(18b), (CH₂)_(q)N(R^(18c))C(O)R¹⁹,     (CH₂)_(r)C(O)OR¹⁹, (CH₂)_(q)OC(O)R¹⁹, (CH₂)_(q)S(O)R¹⁹,     (CH₂)_(q)S(O)₂R¹⁹, (CH₂)_(q)S(O)₂N(R^(18a))R^(18b),     (CH₂)_(q)N(R^(18c))S(O)₂R¹⁹, and (CH₂)_(r)phenyl substituted with     0-3 R¹⁸; -   R¹⁵, at each occurrence, is independently selected from C₁₋₈ alkyl,     (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,     (CHR′)_(r)NR^(15a)R^(15a), (CHR′)_(r)OH,     (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H,     (CHR′)_(r)S(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)     (CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a),     (CHR′)_(r)NR^(15f)C(O) (CHR′)_(r)R^(15b),     (CHR′)_(r)NR^(15f)C(O)NR^(15f)R^(15f),     (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O) (CHR′)_(r)R^(15b),     (CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a),     (CHR′)_(r)NHC(═NR^(15f))NR^(15f)R^(15f), (CHR′)_(r)S(O)     (CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂(CHR′)_(r)R^(15b),     (CHR′)_(r)S(O)₂NR^(15a)R^(15a),     (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈     alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3     R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a     (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4     heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e); -   R′, at each occurrence, is independently selected from H, C₁₋₆     alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and     (CH₂)_(r)phenyl substituted with R^(15e); -   R^(15a), at each occurrence, is independently selected from H, C₁₋₆     alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic     residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-10 membered     heterocyclic system containing 1-4 heteroatoms selected from N, O,     and S, substituted with 0-2 R^(15e); -   R^(5b), at each occurrence, is independently selected from C₁₋₆     alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic     residue substituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered     heterocyclic system containing 1-4 heteroatoms selected from N, O,     and S, substituted with 0-2 R^(15e); -   R^(15d), at each occurrence, is independently selected from C₂₋₈     alkenyl, C₂₋₈ alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(15e), a     (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(15e),     and a (CH₂)_(r)5-6 membered heterocyclic system containing 1-4     heteroatoms selected from N, O, and S, substituted with 0-3 R^(15e); -   R^(15e), at each occurrence, is independently selected from C₁₋₆     alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F,     Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,     (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(15f)R^(15f), and (CH₂)_(r)phenyl; -   R^(15f), at each occurrence, is independently selected from H, C₁₋₆     alkyl, C₃₋₆ cycloalkyl, and phenyl; -   R¹⁶, at each occurrence, is independently selected from C₁₋₈ alkyl,     C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,     NO₂, CN, (CHR′)_(r)NR^(16a)R^(16a), (CHR′)_(r)OH,     (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H,     (CHR′)_(r)S(CHR′)_(r)R^(16d)(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)     (CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a),     (CHR′)_(r)NR^(16f)C(O) (CHR′)_(r)R^(16b),     (CHR′)_(r)C(O)O(CHR′)_(r)R^(16d)(CHR′)_(r)OC(O) (CHR′)_(r)R^(16b),     (CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a),     (CHR′)_(r)NHC(═NR^(16f))NR^(16f)R^(16f), (CHR′)_(r)S(O)     (CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂(CHR′)_(r)R^(16b),     (CHR′)_(r)S(O)₂NR^(16a)R^(16a),     (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈     alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3     R′, and (CHR′)_(r)phenyl substituted with 0-3 R^(16e); -   R^(16a), at each occurrence, is independently selected from H, C₁₋₆     alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic     residue substituted with 0-5 R^(16e), and a (CH₂)_(r)-5-10 membered     heterocyclic system containing 1-4 heteroatoms selected from N, O,     and S, substituted with 0-2 R^(16e); -   R^(16b), at each occurrence, is independently selected from C₁₋₆     alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)C₃₋₆ carbocyclic     residue substituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6 membered     heterocyclic system containing 1-4 heteroatoms selected from N, O,     and S, substituted with 0-2 R^(16e); -   R^(16d) at each occurrence, is independently selected from C₂₋₈     alkenyl, C₂₋₈ alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(16e), a     (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(16e),     and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4     heteroatoms selected from N, O, and S, substituted with 0-3 R^(16e); -   R^(16e), at each occurrence, is independently selected from C₁₋₆     alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F,     Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,     (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(16f)R^(16f), and (CH₂)_(r)phenyl; -   R^(16f), at each occurrence, is independently selected from H, C₁₋₅     alkyl, and C₃₋₆ cycloalkyl, and phenyl; -   R¹⁸, at each occurrence, is independently selected from C₁₋₆ alkyl,     C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅     alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)S(O)C₁₋₅ alkyl,     (CH₂)_(r)S(O)₂C₁₋₅ alkyl, (CH₂)_(r)S(O)₂N(R^(18a))R^(18b),     (CH₂)_(r)N(R^(18c))C(O)C₁₋₅ alkyl (CH₂)_(r)N(R^(18c))S(O)₂C₁₋₅     alkyl, (CH₂)_(r)C(O)N(R^(18a))R^(18b), (CH₂)_(r)C(O)OC₁₋₅ alkyl,     (CH₂)_(r)C(O)C₁₋₅ alkyl, and (CH₂)_(r)N(R^(18a))R^(18b); -   R^(18a), R^(18b), and R^(18c), at each occurrence, are independently     selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; -   alternatively, R^(18a) and R^(18b) along with the nitrogen to which     both are attached form a pyrrolidine, piperidine, piperazine or     morpholine ring; -   R¹⁹, at each occurrence, is independently selected from C₁₋₆ alkyl,     C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R¹⁸; -   R²⁵, at each occurrence, is independently selected from H, C₁₋₆     alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,     (CH₂)_(r)C(O)R¹⁹, (CH₂)_(r)C(O)N(R^(18a))R^(18b), (CH₂)_(r)C(O)OR¹⁹,     (CH₂)_(r)S(O)₂R¹⁹, (CH₂)_(r)S(O)₂N(R^(18a))R^(18b), and     (CH₂)_(r)phenyl substituted with 0-3 R¹⁸; -   a is selected from 0 and 1; -   b is selected from 0, 1, 2 and 3; -   with the proviso that a+b is selected from 1, 2 and 3; -   c is selected from 0 and 1; -   d is selected from 1, 2 and 3; -   with the proviso that c+d is selected from 2 and 3; -   m is selected from 0, 1, and 2; -   s is selected from 0 and 1; -   with the proviso: m+s is selected from 0, 1, and 2; -   v is selected from 0, 1, 2, and 3; -   with the proviso: that the number of atoms in the shortest path     linking the nitrogen to which R⁵ is attached and the fused benzo or     aromatic heterocyclic ring of B contained within such R⁵ is less     than or equal to 4; -   r is selected from 0, 1, 2, 3, 4, and 5; -   t is selected from 0, 1, 2, 3, 4, and 5; -   q is selected from 1, 2, 3, 4, and 5; and -   u is selected from 0, 1 and, 2.

Some preferred compounds are those compounds in which

-   R¹ and R² are independently selected from H and C₁₋₈ alkyl; -   R⁴ is absent, taken with the nitrogen to which it is attached to     form an N-oxide, or selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆     cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted     with 0-3 R^(4c); and -   R^(4c), at each occurrence, is independently selected from C₁₋₆     alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,     CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH,     (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4a)R^(4a), and (CH₂)_(r)phenyl.

Some particularly preferred compounds are those in which

-   Z is selected from O and S; -   R⁶, at each occurrence, is independently selected from C₁₋₄ alkyl,     (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)NR^(6a)R^(6a), (CH₂)_(q)OH,     (CH₂)_(q)OR^(6b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(6b),     (CH₂)_(r)C(O)NR^(6a)R^(6a), (CH₂)_(q)NR^(6d)C(O)R^(6a),     (CH₂)_(r)S(O)₂NR^(6a)R^(6a), (CH₂)_(r)NR^(6d)S(O)₂R^(6b), and     (CH₂)_(t)phenyl substituted with 0-3 R^(6c); -   R^(6a), at each occurrence, is selected from H, methyl, ethyl,     propyl, i-propyl, butyl, cyclopropyl, cyclopentyl, cyclohexyl, and     phenyl; -   R^(6b), at each occurrence, is independently selected from methyl,     ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl,     cyclohexyl, and phenyl; -   R^(6c), at each occurrence, is independently selected from C₁₋₆     alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,     (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and     (CH₂)_(r)NR^(6d)R^(6d); and -   R^(6d), at each occurrence, is independently selected from H,     methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl,     and cyclohexyl.

Some more particularly preferred compounds are those in which

-   R³ is selected from a (CR^(3′)H)_(r)—C₃₋₈ carbocyclic residue     substituted with 0-5 R¹⁵, wherein the carbocyclic residue is     selected from phenyl and naphthyl; and a (CR^(3′)H)_(r)-heterocyclic     system substituted with 0-3 R¹⁵, wherein the heterocyclic system is     selected from pyridinyl, thiophenyl, furanyl, indazolyl,     benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl,     benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl,     indolyl, indolinyl, indazolyl, isoindolyl, isothiadiazolyl,     isoxazolyl, piperidinyl, pyrazolyl, 1,2,4-triazolyl,     1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,     pyrazinyl, and pyrimidinyl; and -   R^(5a) is selected from phenyl substituted with 0-5 R¹⁶; and a     heterocyclic residue substituted with 0-3 R¹⁶, wherein the     heterocyclic system is selected from pyridinyl, thiophenyl, furanyl,     indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,     benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,     isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,     isothiadiazolyl, isoxazolyl, piperidinyl, pyrazolyl,     1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,     thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.

Some yet even more particularly preferred compounds are those in which

-   R¹ and R² are H; -   R^(5a) is phenyl substituted with 1-3 R¹⁶; -   R¹⁶, at each occurrence, is independently selected from C₁₋₈ alkyl,     (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F, NR^(16a)R^(16a), NO₂,     CN, OH, OR^(16d), C(O)R^(16b), C(O)NR^(16a)R^(16a), and     NR^(16f)C(O)R^(16b); -   R^(16a), at each occurrence, is independently selected from H,     methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl,     cyclohexyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e); -   R^(16b), at each occurrence, is independently selected from methyl,     ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl,     cyclohexyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e); -   R^(16d), at each occurrence, is independently selected from methyl,     ethyl, propyl, i-propyl, butyl, and phenyl; -   R^(16e), at each occurrence, is independently selected from methyl,     ethyl, propyl, i-propyl, butyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,     OH, and (CH₂)_(r)OC₁₋₅ alkyl; and -   R^(16f), at each occurrence, is independently selected from H,     methyl, ethyl, propyl, i-propyl, and butyl.

Additional preferred compounds are those compounds in which the compound is a compound of formula (Ia)

Additional particularly preferred compounds are those in which

-   R⁴ is absent; -   R⁵ is

-   R^(11a) and R^(12a), at each occurrence, are independently selected     from H, methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl,     cyclopropyl, cyclopentyl, cylohexyl, CF₃,     (CH₂)_(r)N(R^(18a))R^(18b), (CH₂)_(r)OH; -   R^(11b), R^(12b), R^(14a) and R^(14b), at each occurrence, are     independently selected from H, methyl, ethyl, propyl, i-propyl,     butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cylohexyl, CF₃,     (CH₂)_(q)N(R^(18a))R^(18b), (CH₂)_(q)OH; -   R²⁵, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl,     cyclohexyl, (CH₂)_(r)C(O)R¹⁹, (CH₂)_(r)C(O)N(R^(18a))R^(18b),     (CH₂)_(r)C(O)OR¹⁹, and (CH₂)_(r)phenyl substituted with 0-3 R¹⁸.

Additional more particularly preferred compounds are those in which

-   R⁵ is

-   R^(11a) and R^(12a), at each occurrence, are independently selected     from H, methyl, ethyl and OH; -   R^(11b), R^(12b), R^(14a), and R^(14b), at each occurrence, are     independently selected from H, methyl, and ethyl; and -   R¹⁶, at each occurrence, is independently selected from methyl, Cl,     F, CF₃, and CN.

Additional yet even more particularly preferred compounds are those in which R⁵ is

Additional still yet even more particularly preferred compounds are those in which the compound is selected from the compounds of Tables 1 and 2.

In another embodiment, the present invention relates to pharmaceutical compositions, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention.

In another embodiment, the present invention relates to a method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.

In another embodiment, the present invention provides a method for treating or preventing asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.

In another embodiment, the modulation of chemokine receptor activity comprises contacting a CCR3 receptor with an effective inhibitory amount of a compound of the present invention.

In another embodiment, the present invention provides a method for treating or preventing inflammatory disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for treating or preventing disorders selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin's disease, and colonic carcinoma, preferably asthma, allergic rhinitis, atopic dermatitis, and inflammatory bowel-diseases, more preferably asthma.

In another embodiment, the present invention provides a pharmaceutical composition comprised of a pharmaceutical composition of the present invention and one or more active ingredients.

In another embodiment, the present invention provides a method for treating inflammatory disorders comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention and one or more active ingredients.

It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.

Definitions

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom or ring is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

When any variable (e.g., R^(a)) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R^(a), then said group may optionally be substituted with up to two R^(a) groups and R^(a) at each occurrence is selected independently from the definition of R^(a). Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, “C₁₋₈ alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₈ alkyl, is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkyl groups. “Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. “Alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like. “C₃₋₆ cycloalkyl” is intended to include saturated ring groups having the specified number of carbon atoms in the ring, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C₇ cycloalkyl. C₃₋₆ cycloalkyl, is intended to include C₃, C₄, C₅, and C₆ cycloalkyl groups

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF₃, having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

As used herein, the term “5-6-membered cyclic ketal” is intended to mean 2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane and their derivatives.

As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S.

Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. Heterocycles include, but are not limited to, pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

The compounds herein described may have asymmetric centers. While all enantiomers/diasteriomers are intended to be covered by the instant application, one enantiomer of a compound of Formulas (Ia) and/or (Ib) may display superior biological activity over the opposite enantiomer. When required, separation of the racemic material can be achieved by methods known in the art. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. “Prodrugs” are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

In addition, compounds of the formula I are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% formula I compound (“substantially pure” compound I), which is then used or formulated as described herein. Such “substantially pure” compounds of the formula I are also contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are envisioned for this invention.

“Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to treat the inflammatory diseases described herein.

As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.

Sythesis

The compounds of Formula Ia and Formula Ib can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. It will sometimes be desirable or necessary to modify the order of the synthetic steps or to select one particular process over another in order to obtain a desired compound of the invention, and such modifications will be recognized by those skilled in the art. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. Multiple protecting groups within the same molecule can be chosen such that each of these protecting groups can either be removed without removal of other protecting groups in the same molecule, or several protecting groups can be removed using the same reaction step, depending upon the outcome desired. An authoritative account describing many alternatives to the trained practitioner is T. W. Greene and P. G. M. Wuts, Protective Groups In Organic Synthesis, Wiley and Sons, 1999. Some protecting groups are also discussed in M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 2nd ed., Springer-Verlag, 1994; and M. Bodanszky, Peptide Chemistry, 2nd ed., Springer-Verlag, 1993.

The various substituents on the synthetic intermediates and final products shown in the following reaction schemes can be present in their fully elaborated forms, with suitable protecting groups where required as understood by one skilled in the art, or in precursor forms which can later be elaborated into their final forms by methods familiar to one skilled in the art. The substituents can also be added at various stages throughout the synthetic sequence or after completion of the synthetic sequence. In many cases, commonly used functional group manipulations can be used to transform one intermediate into another intermediate, or one compound of formula Ia into another compound of formula Ia, or one compound of formula Ib into another compound of formula Ib. Examples of such manipulations are conversion of an ester or a ketone to an alcohol; conversion of an ester to a ketone; interconversions of esters, acids, and amides; alkylation, acylation, and sulfonylation of alcohols and amines; and many others. Substituents can also be added using common reactions such as alkylation, acylation, halogenation, or oxidation. Such manipulations are well known in the art, and many reference works summarize procedures and methods for such manipulations. Some reference works which gives examples and references to the primary literature of organic synthesis for many functional group manipulations as well as other transformations commonly used in the art of organic synthesis are R. C. Larock, Comprehensive Organic Transformations, VCH, 1989; A. Katritzky et al. (series editors), Comprehensive Organic Functional Group Transformations, Pergamon, 1995; and B. Trost and I. Fleming (series editors), Comprehensive Organic Synthesis, Pergamon, 1991.

Generally, compounds of Formula Ia can be synthesized by the routes described in Schemes 1, 2, or 3. In all schemes, P and P′ are suitable protecting groups such as those described in T. W. Greene and P. G. M. Wuts, Protective Groups In Organic Synthesis, John Wiley and Sons, 1999; M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 2nd ed., Springer-Verlag, 1994; or M. Bodanszky, Peptide Chemistry, 2nd ed., Springer-Verlag, 1993.

In Scheme 1, an appropriately substituted protected bicyclic amine 1 can be alkylated by reaction with an appropriate alkyl halide (X=Cl, Br, I) or activated alkyl alcohol (for example, X=methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, or other leaving group capable of reacting with a nucleophilic amine) 2 to provide the protected bicyclic amine 3. The alkylation reaction can be performed with or without the addition of an acid scavenger or base such as carbonate and bicarbonate salts, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropylethylamine (Hünig's base), 4-(N,N-dimethylamino)pyridine (DMAP), and the like. If the alkylating agent 2 is not an alkyl iodide, then potassium iodide can be added to facilitate the alkylation reaction if the solvent and reactants are compatible with such an additive. The reaction can be performed in a suitable solvent such as an alcohol, acetonitrile, acetone, 2-butanone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidinone, or dimethyl sulfoxide (DMSO), among others, and can be performed at a temperature in the range of room temperature to the reflux temperature of the solvent. The amine protecting group P can subsequently be removed to provide the amine 4. Protecting groups include phthalimide which can be removed by treatment with hydrazine; tert-butyloxycarbonyl (Boc) or bis-Boc which can be removed by treatment with an appropriate acid such as trifluoroacetic acid or hydrochloric acid in a suitable solvent; benzyloxycarbonyl (carbobenzyloxy or Cbz) which can be removed by a variety of catalytic reduction methods familiar to one skilled in the art; benzyl, diphenylmethyl or triphenylmethyl (trityl) or substituted variants of these groups which can also be removed by reduction methods; 2,4-dimethylpyrrole (S. P. Breukelman et al., J. Chem. Soc. Perkin Trans. I, 1984, 2801); N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE) (S. Djuric, J. Venit and P. Magnus, Tetrahedron Lett. 1981, 22, 1787); and other protecting groups.

Reaction of the amine 4 with an isocyanate or isothiocyanate 5 (Z=O or S) or with a carbamoyl chloride 6 (X′=Cl), phenyl carbamate 6 (X′=phenoxy) or 2- or 4-nitrophenyl carbamate 6 (X′=2- or 4-nitrophenoxy), or their thiocarbonyl equivalents, yields urea or thiourea 7. Reaction of 4 with a chloroformate or chlorothioformate 8 (Z=O or S) such as 2- or 4-nitrophenyl chloroformate or phenyl chloroformate (X″=2- or 4-nitro or H) or their thiocarbonyl equivalents, followed by treatment of the intermediate 9 with an amine 10, also yields the corresponding urea or thiourea 7. Likewise, reaction of carbamate 9 (X″=H, or 2- or 4-nitro) with disubstituted amine 11 yields trisubstiuted urea or thiourea 12. Reaction of the amine 4 with an N,N-disubstituted carbamoyl chloride 13 (X′=Cl), phenyl carbamate 13 (X′=phenoxy) or 2- or 4-nitrophenyl carbamate 13 (X′=2- or 4-nitrophenoxy), or their thiocarbonyl equivalents, also provides the corresponding N,N-disubstituted urea or thiourea 12.

Amine 4 can also be reductively alkylated with an aldehyde 14 to yield 15 by conditions familiar to one skilled in the art such as those reported in A. F. Abdel-Magid et al., Tetrahedron Lett. 1990, 31, 5595. This secondary amine can subsequently be reacted as described for reactions of 4 with isocyanates or isothiocyanates or carbamoyl chlorides or carbamates to provide trisubstituted ureas 16 or with carbamoyl chlorides or carbamates to yield tetrasubstituted ureas 17.

Amine 4 can also be converted into an isocyanate, isothiocyanate, carbamoyl chloride or thiocarbamoyl chloride (these reactions are not shown in Scheme 1). Examples of methods for such conversions can be found in J. Nowakowski, J. Prakt. Chem. 196, 338, 667; H.-J. Knoelker et al., Angew. Chem. 1995, 107, 2746; J. S. Nowick et al., J. Org. Chem. 1996, 61, 3929; H. A. Staab and W. Benz, Angew. Chem. 1961, 73 (for isocyanates); L. Strekowski et al., J. Heterocyclic Chem. 1996, 33, 1685; P. Kutschy et al., Synlett 1997, 289 (for isothiocyanates); F. Hintze and D. Hoppe, Synthesis 1992, 1216 (for carbamoyl chlorides); and W. Ried, H. Hillenbrand and G. Oertel, Justus Liebigs Ann. Chem. 1954, 590 (for thiocarbamoyl chlorides). These isocyanates, isothiocyanates, carbamoyl chlorides or thiocarbamoyl chlorides can then be reacted with R²R³NH to provide di- or trisubstituted ureas or thioureas 13. An additional urea forming reaction involves the reaction of carbonyldiimidazole (CDI; J. L. Romine et al., Synthesis 1994, 846) with 4, followed by reaction of the intermediate imidazolide with 10 or in the reversed sequence (reaction of 10 with CDI, followed by treatment of the intermediate with 4). Activation of imidazolide intermediates facilitates urea formation (R. A. Bailey et al., Tetrahedron Lett. 1998, 39, 6267). One can also use 15 and 11 with CDI.

The reactions leading to formation of the ureas or thioureas can be done in aprotic inert solvents such as tetrahydrofuran, toluene, N,N-dimethylformamide, and the like, at a temperature in the range of room temperature to the reflux temperature of the solvent, and can employ the use of an acid scavenger or base such as carbonate and bicarbonate salts, triethylamine, DBU, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine, and the like.

Scheme 2 describes alternative methods for attachment of certain selections of R⁵. Reaction of amine 1 with an aldehyde 18 (R=H) or ketone 18 (R=R^(14a) or R^(13b) in the compounds of Formula Ia, or R and R′ taken together form a ring as shown for certain selections of R⁵ in the compounds of Formula Ia) in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, or a polymer-supported form of the cyanoborohydride anion, provides 19, where R(R′)CH is certain of the selections of R⁵ in the compounds of Formula (Ia); that is, the point of attachment of R⁵ to the ring nitrogen must bear at least one hydrogen. Such reductive alkylation of amines is well known in the art of organic synthesis, and can be achieved using reagents, solvents and reaction conditions described in, for example, R. O. Hutchins and M. K. Hutchins in B. N. Trost and I. Fleming, Comprehensive Organic Chemistry, Pergamon Press: New York, 1991, vol. 8; A. F. Abdel-Magid et al., J. Org. Chem. 1996, 61, 3849; or R. O. Hutchins et al., J. Chem. Soc. Chem. Commun., 1978, 1088. The protecting group of 19 can then be removed and the urea or thiourea can be prepared from the resulting amine 20 using the procedures outlined in Scheme 1.

Scheme 2 also demonstrates another method for the preparation of amines 19 where R′=H and RR′CH is certain of the selections of R⁵ in the compounds of Formula (Ia); that is, the point of attachment of R⁵ to the piperidine nitrogen must bear two hydrogens. This method involves the acylation of amine 1 with a carboxylic acid 21 (X=OH) or the derived carboxylic acid chloride 21 (X=Cl) or a derived mixed anhydride 21 (X=OC(═O)OR″, where R″ is an alkyl group) to provide the amide 22. Such amide-forming reactions can be achieved using a wide variety of reagents and conditions known to one skilled in the art, such as for example the methods described in M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 2nd ed., Springer-Verlag: New York, 1994; and M. Bodanszky, Peptide Chemistry, 2nd ed., Springer-Verlag: New York, 1993. Conversion of a carboxylic acid to the derived carboxylic acid chloride or mixed anhydride (21, X=Cl or OC(═O)OR′) can be achieved using a variety of conditions and reagents well known to one skilled in the art, such as for example using thionyl chloride, phosphorus pentachloride, oxalyl chloride, or an alkyl chloroformate such as isobutyl chloroformate. (See, for example, the above-cited references by Bodanszky, as well as Ansell in S. Patai, The Chemistry of Carboxylic Acids and Esters, Wiley Interscience: New York, 1969, 35-68.)

The amide 22 can be converted to the amine 19 (R′=H) using a reducing agent such as borane or lithium aluminum hydride, a reaction well known to one skilled in the art. Such reductions can be carried out in a solvent such as a dialkyl ether or tetrahydrofuran, at a temperature in the range 0° C. to the boiling point of the solvent. The resulting amine 19 can then be deprotected to provide 20 (R′=H), which can be converted to the urea or thiourea using the procedures outlined in Scheme 1.

Compounds of Formula (Ia) can also be prepared using the sequence of reactions shown in Scheme 3. A protected bicyclic diamine 23 can be converted to the urea or thiourea 24 using one of the methods depicted in Scheme 1 for the conversion of 4 to 7, 12, 16 or 17. The protecting group can be removed, and the resulting amine 25 can be alkylated using one of the methods depicted in Schemes 1 and 2 to provide the desired compound.

Guanidines of Formula Ia (Z=NR^(d)) can be synthesized by the methods outlined in Scheme 4. Compound 26 can be methylated to yield the methylisothiourea 27. Displacement of the thiomethyl group with amines can provide substituted guanidines 28 (as reported by H. King and I. M. Tonkin, J. Chem. Soc. 1946, 1063; and references cited therein). Alternatively, reaction of thiourea 26 with amines in the presence of triethanolamine and lac sulfur which facilitates the removal of hydrogen sulfide can provide substituted guanidines 28 (as reported by K. Ramadas, Tetrahedron Lett. 1996, 37, 5161 and references cited therein). The use of carbonimidoyldichloride 29 or 30 followed by sequential displacements by amines provides the corresponding substituted guanidine 28 (as reported by S. Nagarajan et al., Synth. Commun., 1992, 22, 1191, and references cited therein). In a similar manner, carbonimidoyldichlorides R²—N═C(Cl)₂ and R³—N═C(Cl)₂ (not shown in Scheme 4) can also be reacted sequentially with amines to yield di- and trisubstituted guanidine 28.

Compounds of Formula Ia where Z=N—CN, CHNO₂, and C(CN)₂ can be synthesized by the methods shown in Scheme 5. For example, following the method reported by P. Traxler et al., J. Med. Chem. 1997, 40, 3601, amine 31 can react with malononitrile 32 in an inert solvent or neat, at a temperature in the range of room temperature to the boiling point of the solvent, or at the melting point of the solid/solid mixture, to provide the malononitrile 33. This in turn can undergo reaction with amine 15 under similar conditions to those given above to give malononitrile 34. Likewise, a similar reaction sequence can be used to prepare 37 (see, for example, J. Hoffman et al., J. Med. Chem. 1983, 26, 140) and 40 (see, for example, K. Atwal, J. Med. Chem. 1998, 41, 271).

The synthetic methods illustrated in Schemes 1 through 5 can also be used to prepare compounds of Formula Ib. Examples of this are shown in Scheme 6. The protected bicyclic amine 41 can be alkylated with an aldehyde or ketone 18, as described for Scheme 2, to provide the substituted amine 42. This amine can optionally be alkylated again, using methods described for Schemes 1 and 2, to provide 43, where R⁵ is equivalent to CH(R)R′ of 42. (Alternatively, if desired, the secondary amine of 42 can be protected using a suitable protecting group.) Removal of the protecting group of 43 can provide the cyclic amine 44, which can be converted to the urea or related compound 45 using methods shown in Schemes 1, 4 or 5.

Another approach to compounds of Formula Ib, also shown in Scheme 6, involves reductive amination of the ketone 46 with an amine NHR⁵R^(5′), using methods known in the literature as described for Schemes 1 and 2. The resulting amine 43 can then be converted to 45 by deprotection and conversion to the urea or related compound, as already described.

Many amines are commercially available and can be used as 10, 11, and the amines which are precursors to isocyanates or isothiocyanates 5 or carbamoyl chlorides, phenyl carbamates or 2- or 4-nitrophenylcarbamates 6 and 13, as well as other amines whose use is illustrated in Schemes 1 through 6. There are numerous methods for the synthesis of non-commercially available amines familiar to one skilled in the art. For example, aldehydes and ketones can be converted to their o-benzyl oximes and then reduced with lithium aluminum hydride to provide amines (S. Yamazaki et al., Bull. Chem. Soc. Japan 1986, 59, 525). Ketones and trifluoromethyl ketones undergo reductive amination in the presence of titanium (IV) chloride followed by sodium cyanoborohydride to yield amines (C. Barnet et al., Tetrahedron Lett., 1990, 31, 5547). Aldehydes and ketones undergo reductive amination with sodium triacetoxyborohydride and amines to yield other amines (A. Abdel-Magid et al., J. Org. Chem. 1996, 61, 3849). Aryl amines can be synthesized from aromatic and heterocyclic hydroxyl groups (for example, phenols) using the Smiles rearrangement (J. Weidner and N. Peet, J. Heterocyclic Chem. 1997, 34, 1857). Displacement of halides, p-toluenesulfonates, methanesulfonates, trifluoromethanesulfonates, and the like with azide or cyanide followed by reduction with lithium aluminum hydride or catalytic hydrogenation or other reduction methods yields amines. Sodium diformyl amide (H. Yinglin and H. Hongwen, Synthesis 1989, 122), potassium phthalimide and bis-Boc-amine anion can all displace halides and other leaving groups, followed by standard deprotection methods to yield amines. Other methods to synthesize more elaborate amines involve the Pictet-Spengler reaction, imine/immonium ion Diels-Alder reactions (S. Larsen and P. Grieco, J. Amer. Chem. Soc., 1985, 107, 1768; P. Grieco et al., J. Org. Chem. 1988, 53, 3658; J. Cabral and P. Laszlo, Tetrahedron Lett., 1989, 30, 7237), amide reduction for example with lithium aluminum hydride or borane, organometalic addition to imines (A. Bocoum et al., J. Chem. Soc. Chem. Commun., 1993, 1542), and others which are familiar to one skilled in the art. (Additional methods for amine preparation are described further in the discussion of Scheme 9 below.)

Various aromatic amines can be synthesized using the methods shown in Scheme 7. For example, nitrobenzeneboronic acids 47 can undergo Suzuki-type coupling reactions with a wide variety of substituted iodo-, bromo-, chloro-, or trifluoromethanesulfonyloxy-substituted arenes (arene representing phenyl, naphthyl, and the like), aromatic heterocycles, alkanes, alkenes, or alkynes 48 (X=I, Br, Cl, or CF₃SO₃; R=optionally substituted aryl, heteroaryl, alkyl, alkenyl, or alkynyl) (see, for example, A. Suzuki, Pure Appl. Chem. 1991, 63, 419; J.-M. Fu and V. Snieckus, Tetrahedron Lett., 1990, 31, 1665; and M. Moreno-Manas et al., J. Org. Chem. 1995, 60, 2396) to provide 49. The above reactions can also undergo carbonyl insertion in the presence of an atmosphere of carbon monoxide (Ishiyama et al., Tetrahedron Lett., 1993, 34, 7595) to provide 51. Arylboronic acids 47 can also be coupled with amines 53 (R=alkyl, aryl, heteroalkyl; X′=NH), amides 53 (R=alkylcarbonyl, arylcarbonyl, and the like; X′=N-alkyl or N-aryl), sulfonamides 53 (R=alkylsulfonyl, arylsulfonyl and the like; X′=N-alkyl), phenols 53 (R=aryl, X′=O) or NH-containing heteroarenes 53 (X′=N, with R representing the remainder of a heteroarene such as pyrazole, imidazole, triazole, indazole and the like) to provide the corresponding coupled products 54 (D. Chan et al., Tetrahedron Lett., 1998, 39, 2933; P. Lam et al., Tetrahedron Lett., 1998, 39, 2941; P. Lam et al., Synlett 2000, 674).

The resulting nitro-containing compounds of Scheme 6 (49, 51 and 54) can then be reduced to the corresponding amines 50, 52 and 55 either using catalytic hydrogenation, or using a number of chemical methods well known in the art, for example with tin (II) chloride, iron or tin with an acid, titanium (III) chloride, or ammonium sulfide. The carbonyl insertion compounds 51 and 52 can also undergo reduction of the carbonyl group to either CH(OH) or CH₂ linkages using methods well known in the art, for example with sodium borohydride or triethylsilane with trifluoroacetic acid.

Aromatic amines can also be prepared as shown in Scheme 8. Protected aminobromobenzenes or protected aminophenyl trifluoromethanesulfonates 56, or heterocyclic analogs of 56, can undergo Suzuki-type couplings with arylboronic acids or heteroarylboronic acids 57 (R=aryl or heteroaryl). These same bromides or trifluoromethanesulfonates 56 can also undergo Stille-type couplings (A. Echavarren and J. Stille, J. Amer. Chem. Soc. 1987, 109, 5478) with aryl, alkenyl, or heteroaryl stannanes 58 (R=aryl, heteroaryl, or alkenyl). Bromides or trifluoromethanesulfonates 56 can also undergo Negishi-type couplings (E. Negishi, Accts. Chem. Res. 1982, 15, 340; M. Sletzinger et al., Tetrahedron Lett., 1985, 26, 2951) with aryl, heteroaryl, alkyl or alkenyl zinc bromides or iodides 59 (R=aryl, heteroaryl, alkyl or alkenyl; X′=Br or I). Bromides, chlorides or trifluoromethanesulfonates 56 can also undergo couplings with amines 62 (R=alkyl or aryl, X″=NH, N-alkyl, and the like), carbamates 62 (R=alkoxycarbonyl, X″=NH), alcohols 62 (R=alkyl, X″=O) or phenols 62 (R=aryl, X″=O) to provide the corresponding amines, carbamates, or ethers 63 (see, for example, J. Hartwig, Angew. Chem. 1998, 37, 2046; J. Hartwig et al., J. Org. Chem. 1999, 64, 5575; J. Wolfe et al., J. Org. Chem. 2000, 65, 1158; and J. Wolfe and S. Buchwald, J. Org. Chem. 2000, 65, 1144). The protected amines 60 or 63 resulting from these various coupling reactions can be deprotected to provide amines 61 or 64, respectively.

Aromatic amines bearing certain heteroaryl substituents linked through a carbon atom can also be prepared as shown in Scheme 9. Benzoic acid derivatives 65 (X′=nitro or protected amine) can be reacted with a variety of reagents to prepare a variety of five-membered ring heteroaryl-substituted compounds 66. A few examples known in the literature are described, but are not to be considered limitations on the method shown in Scheme 9. Reaction of amide 65 (X=NH₂) with triazidochlorosilane can provide tetrazole 66 (Y¹=NH, Y² and Y³=N) (A. El-Ahl et al., Tetrahedron Lett., 1997, 38, 1257). Reaction of amide 65 (X=NH-alkyl) with azidotrimethylsilane can provide tetrazole 66 (Y¹=N-alkyl, Y² and Y³=N) (J. Duncia et al., J. Org. Chem. 1991, 56, 2395). Reaction of hydrazide 65 (X=NHNH₂) with an acylating agent, followed by dehydration, can provide oxadiazole 66 (Y¹=O, Y²=C-alkyl or C-aryl, Y³=N); further reaction of this oxadiazole with an amine can provide triazole 66 (Y¹=N-alkyl, Y² =C-alkyl or C-aryl, Y³ =N) (P. Carlsen and K. Joergensen, J. Heterocyclic Chem. 1994, 31, 805). Reaction of an acid chloride 65 (X=Cl) with an imidate ester iminophosphorane derived from azidoacetonitrile can provide imidazole 66 (Y¹=NH, Y² and Y³=CH or C-alkyl) (P. Molina et al., Synthesis 1995, 449). Reaction of a acylated glycine 65 (X=N(alkyl)CH₂COOH) with a carboxylic acid anhydride, followed by treatment with a guanidine or ammonium acetate, can provide imidazole 66 (Y¹=NH, Y²=C-alkyl or C-aryl, Y³=C-alkyl, C-aryl or CH) (M. Kawase et al., Heterocycles 1995, 41, 1617). Reaction of an acid or acid chloride 65 (X=OH or Cl) with an ortho-phenylenediamine or an ortho-aminophenol can provide benzimidazole 66 (Y¹=NH, Y² and Y³ are carbon with a benzene ring fused to the Y²—Y³ bond) or benzoxazole 66 (Y¹=O, Y² and Y³ are carbon with a benzene ring fused to the Y²—Y³ bond) (M. DeLuca and S. Kerwin, Tetrahedron 1997, 53, 457). Reaction of an acid chloride 65 (X=Cl) with an aziridine-2-carboxylic acid ester, followed by rearrangement of the amide and oxidation, can provide oxazole 66 (Y¹=O, Y²=CH, Y³=C—COO-alkyl) (F. Eastwood et al., J. Chem. Soc. Perkin Trans. I 1997, 35). The thioamide corresponding to 65 (X=NH₂, with the carbonyl oxygen replaced by sulfur) can react with an alpha-bromoketone to provide thiazole 66 (Y¹=S, Y² and Y³=CH, C-alkyl or C-aryl) (O. Uchikawa et al., Chem. Pharm. Bull., 1996, 44, 2070). Reaction of acid chloride 65 (X=Cl) with a beta-hydroxyamine, followed by treatment with phosphorus pentasulfide and oxidation, can also provide thiazole 66 (Y¹=S, Y² and Y³ are CH, C-alkyl or C-aryl) (R. Aitken et al., J. Chem. Soc. Perkin Trans. I 1997, 935). The protected amines 66 (X′=NHP) or nitrobenzenes 66 (X′=NO₂) resulting from these various reactions and others like them can be deprotected or reduced, respectively, as described for Schemes 7 and 8, to provide amines 67.

The amines described above (commercially available, or prepared as described in Schemes 7, 8 and 9, and other amines) can be converted to isocyanates 5 (Z=O) using methods such as those reported by J. Nowakowski, J. Prakt. Chem. 1996, 338, 667; H. J. Knoelker et al., Angew. Chem. 1995, 107, 2746; J. Nowick et al., J. Org. Chem. 1996, 61, 3929; and H. Staab and W. Benz, Angew. Chem. 1961, 73. They can also be converted to isothiocyanates 5 (Z=S) using methods such as those reported by L. Strekowski et al., J. Heterocyclic Chem. 1996, 33, 1685; and P. Kutschy et al., Synlett 1997, 289. They can also be converted (after optional reductive alkylation with an R² group) to carbamoyl chlorides 6 or 13 (X′=Cl, Z=O), for example as reported by F. Hintze and D. Hoppe, Synthesis 1992, 1216; to thiocarbamoyl chlorides 6 or 13 (X′=Cl, Z=S), for example as reported by W. Ried et al., Justus Liebigs Ann. Chem. 1954, 590; or to phenyl or 2- or 4-nitrophenylcarbamates 6 or 13 (X′=phenoxy, 2-nitrophenoxy or 4-nitrophenoxy; Z=O) by treatment with the corresponding phenyl, 2-nitrophenyl or 4-nitrophenyl chloroformate under suitable conditions known to one skilled in the art.

The bicyclic diamines and protected forms thereof (1 in Schemes 1 and 2, 23 in Scheme 3, and 41 in Scheme 6) can be prepared using a variety of methods, as described in Schemes 10 and 12. Compounds 4 and 15 of Scheme 1 and 20 of Scheme 3 can also be prepared by the methods in Schemes 10 and 12. If the ring nitrogen of any of these intermediates is protected with an amine protecting group, this protecting group can be removed at any step of the reaction sequences shown and replaced by a group R⁵ of Formula Ia, using one of the alkylation methods described in Schemes 1, 2, or 3 or another method, as long as the deprotection and alkylation reactions are compatible with the structure of the intermediate upon which the reactions are performed, and as long as the resulting R⁵-substituted intermediate is compatible with the remaining reactions in the sequence. Likewise, in some of the reaction sequences shown in Schemes 10 and 12, it may be possible to substitute a group R⁵ of Formula Ia for the protecting group on the ring nitrogen, providing direct access to 4 or 20. Such cases will be apparent to one skilled in the art.

One method for the preparation of bicyclic diamines and suitably protected forms thereof (such as 1 in Schemes 1 and 2, 23 in Scheme 3, and 41 in Scheme 6), shown in Scheme 10, involves conversion of a carboxylic acid 68 (R=OH) or carboxylic acid derivative such as an acid chloride 68 (R=Cl) or mixed anhydride 68 (R=OC(═O)alkyl or OC(═O)Oalkyl) into an acyl azide 69, followed by thermal rearrangement to the isocyanate 70, commonly referred to as the Curtius rearrangement. Treatment of the intermediate isocyanate with water can provide the amine 71 directly. Alternatively, treatment of the intermediate isocyanate with an alcohol such as benzyl alcohol can provide the carbamate 72, which can serve as a protected form of the amine 71 and either deprotected to provide 71 or used directly, for example as described for Schemes 1 and 2. Alternatively, the isocyanate 70 can sometimes be isolated, in which case it can be treated with an amine to form a urea as discussed previously. Some examples of the use of the Curtius rearrangement to effect transformations analogous to those shown in Scheme 10 have been reported by J. Altman and D. Ben-Ishai, Tetrahedron Asymmetry 1994, 5, 887; K. Ninomiya, T. Shioiri and S. Yamada, Tetrahedron 1974, 30, 2151; L. M. Gustavson and A. Srinivasan, Synth. Commun., 1991, 21, 265; R. Pires and K. Burger, Synthesis 1996, 1277; and E. Neufellner, H. Kapeller and H. Griengl, Tetrahedron 1998, 54, 11043.

A related method for achieving the transformation of a carboxylic acid derivative to an amine as shown in Scheme 10 involves treatment of an amide 68 (R=NH₂) with an oxidizing agent such as sodium hypobromite or I,I-bis-(trifluoroacetoxy)iodobenzene to provide the amine 71, a reaction commonly referred to as the Hofmann rearrangements. This transformation is reviewed by Wallis and Lane, Org. Reactions 1946, 3, 267; a more recent example was reported by Radhakrishna et al., J. Org. Chem. 1979, 44, 1746.

The carboxylic acids and derivatives 68 can be prepared using methods well known in the art of organic synthesis. For example, as shown in Scheme 11, a carboxylate ester 74 can be prepared by the Diels-Alder reaction of a 3-vinyl-1,4,5,6-tetrahydropyridine 73 with an acrylate ester, as reported by C. Ludwig and L. G. Wistrand, Acta Chem. Scand., 1989, 43, 676. Also shown in Scheme 11 is another example, involving the intramolecular Diels-Alder reaction of 75 to provide the ester 76, as reported by S. Wattarasin, F. G. Kathawala and R. K. Boeckman, J. Org. Chem. 1985, 50, 3810. These are not the only methods by which carboxylate acids and carboxylate derivatives 68 can be prepared, but serve as examples of methods by which such derivatives can be prepared.

Another method for the preparation of bicyclic diamines and suitably protected forms thereof (such as 1 in Schemes 1 and 2, 23 in Scheme 3, and 41 in Scheme 6) is by conversion of a ketone such as 77 to the oxime or substituted oxime 78 (X′=OH or O-benzyl, for example) or an imine 78 (X′=R¹) followed by reduction to an amine 79 (R^(6′)=H) using a reducing agent such as lithium aluminum hydride or borane, as shown in Scheme 12. Alternatively, the oxime or substituted oxime or imine 78 can be treated with an organometallic reagent such as R^(6′)Li or R^(6′)MgBr, followed by reductive cleavage of the N—O bond in the cases of oximes or substituted oximes, to provide amines 79 where R^(6′) is one of the R⁶ substituents. (In the cases of oximes and substituted oximes, the R¹ of 79 will be H.) This type of transformation is well known in the literature of organic chemistry. References to some examples are given in R. C. Larock, Comprehensive Organic Transformations, VCH, 1989.

Ketones 77 can also be converted to amines by reductive amination, using well known procedures as discussed previously, to provide amines 80. The same procedure can be used to provide amines 81 useful as intermediates 43, as described in Scheme 6.)

Alternatively, ketones 77 can be converted to alcohols 82 by reduction using reagents such as sodium borohydride or lithium aluminum hydride. The alcohols 82 can be converted to the primary amines 80 (R¹=H) using several methods, for instance by conversion of the hydroxyl group to a leaving group such as methanesulfonate, trifluoromethanesulfonate or p-toluenesulfonate; displacement of the leaving group with an appropriate nucleophile such as azide anion; and reduction of the resulting azide to an amine using, for example, a method such as catalytic hydrogenation or reduction with triphenylphosphine followed by hydrolysis of the intermediate iminophosphorane with water. Examples of these transformations can be found in K. Hilpert et al., J. Med. Chem. 1994, 37, 3889; C. Lebarbier et al., Synthesis 1996, 1371; and M. Rubiralta et al., Synth. Commun., 1992, 22, 359. The alcohols 82 can also be converted directly to the corresponding azides with reagents such as hydrazoic acid or diphenylphosphoryl azide in the presence of a dialkyl azodicarboxylate and triphenylphosphine, for example as described in B. Lal et al., Tetrahedron Lett., 1977, 1977; or J. Hiebl et al., J. Med. Chem. 1991, 34, 1426.

Ketones 77 (equivalent to 46 in Scheme 6) may be prepared using a wide variety of synthetic methods as reported in the literature of organic chemistry. For example, the carboxylic acids 68 (R=OH) show in Scheme 10 may be converted to the corresponding ketones 77 using the oxidative decarboxylation method reported by H. Wasserman and B. H. Lipshutz, Tetrahedron Lett., 1975, 4611. Numerous other methods have been reported for preparation of the bicyclic ring systems corresponding to the ketones 77, with various substitution on the rings and various protecting groups or substitution on the ring nitrogen. In some cases, the reported methods can directly yield the desired ketones 77. In other cases, minor modifications of the reported methods, which will be obvious to one skilled in the art of organic synthesis, can yield the desired ketones 77. In still other cases, simple synthetic transformations of the reported products, obvious to one skilled in the art, can yield the desired ketones 77. Some examples of such methods are listed below.

Ketones 77 (a=0; b=0, 1, or 2; c=0; d=3) can be prepared by cyclization of a 2-(3-aminopropyl)cyclopentanone derivative followed by hydroboration and oxidation (L. E. Overman, G. M. Robertson, and A. J. Robichaud, J. Amer. Chem. Soc. 1991, 113, 2598; L. E. Overman et al., Tetrahedron 1981, 37, 4041) or by cyclization of a 2-cyano-3-(2-alkoxycarbonylethyl)piperidine derivative followed by acid hydrolysis and decarboxylation (C. H. Heathcock, M. H. Norman and D. A. Dickman, J. Org. Chem. 1990, 55, 798). Ketones 77 (a=0; b=1, 2 or 3; c=1; d=1) can be prepared by reaction of an iminiumylide with a 2-cycloalkenone (Eur. Pat. Appl. 0 359 172 A1; M. Ogata et al., Eur. J. Med. Chem. 1991, 26, 889; O. Tsuge et al., Bull. Chem. Soc. Japan 1987, 60, 4079; K. Miyajima, M. Takemoto and K. Achiwa, Chem. Pharm. Bull., 1991, 39, 3175). Ketones 77 (a=0; b=1; c=1; d=2) can be prepared by hydroboration of a 4-vinyl-1,2,5,6-tetrahydropyridine derivative, followed by reaction with potassium cyanide and oxidation (M. Ogata et al., Eur. J. Med. Chem., 1991, 26, 889).

Ketones 77 (a=0; b=2; c=1; d=2) can be prepared by reduction of an 8-nitroisoquinoline derivative followed by subsequent synthetic manipulations (I. W. Mathison and P. H. Morgan, J. Org. Chem. 1974, 39, 3210). Ketones 77 (a=0; b=1, 2 or 3; c=0; d=2) can be prepared by cyclization of an N-bromo-3-(2-aminoethyl)cycloalkene derivative (E. J. Corey, C. P. Chen and G. A. Reichard, Tetrahedron Lett., 1989, 30, 5547) or iodine-induced cyclization of a cycloalken-3-ylacetamide derivative (S. Knapp and A. T. Levorse, J. Org. Chem. 1988, 53, 4006) followed by subsequent synthetic manipulations, or by radical cyclization of a 2,2-dichloro-N-(1-oxocycloalk-2-en-2-yl)acetamide, followed by subsequent synthetic manipulations (A. F. Parsons and D. A. J. Williams, Tetrahedron 2000, 56, 7217).

Ketones 77 (a=1; b=0; c=1; d=2) can be prepared by the intramolecular Pauson-Khand reaction of an appropriately substituted 4-aza- or 5-aza-oct-1-ene-7-yne derivative (G. L. Bolton, J. C. Hodges and J. R. Rubin, Tetrahedron 1997, 53, 6611; B. L. Pagenkopf et al., Synthesis 2000, 1009), or by the Schmidt reaction of tetrahydropentalene-2,5(1H, 3H)-dione (G. Vidau et al., Tetrahedron Asymm. 1997, 8, 2893; V. Gracias et al., Tetrahedron 1997, 53, 16241) followed by subsequent synthetic manipulations. Ketones 77 (a=1; b=1; c=1; d=2) can be prepared by the ring-closing metathesis reaction of a 3,4-diallylpiperidine derivative followed by hydroxylation of the resulting 1,2,3,4,4a,5,8,8a-octahydroisoquinoline (S. Liras, M. P. Allen and J. F. Blake, Org. Lett., 2001, 3, 3483).

Ketones 77 (a=1; b=0; c=0; d=2) can be prepared by Dieckmann cyclization of an appropriate dialkyl 2,2′-pyrrolidine-2,3-diyldiacetate derivative (C. L. J. Wang, Tetrahedron Lett., 1983, 24, 477) or by cyclization of the acyliminium ion derived from an appropriate 3-{2-[(trialkylsilyl)methyl]prop-2-en-1-yl}pyrrolidin-2-one derivative (J. C. Gramain and P. Remuson, Heterocycles 1989, 29, 1263). Ketones 77 (a=1; b=1; c=0; d=2 or 3) can be prepared by dissolving metal reduction of an appropriate 4-alkoxyphenethylamine or 4-alkoxyphenpropylamine derivative, followed by hydrolysis and cyclization (J. Bonjoch et al., Tetrahedron Asymm., 1997, 8, 3143; U.S. Pat. No. 4,600,777; T. Momose et al., Chem. Pharm. Bull., 1977, 25, 1797) or by dissolving metal reduction of an appropriate 6-alkoxyindoline derivative followed by hydrolysis and double bond reduction (H. Iida, Y. Yuasa and C. Kibayashi, J. Org. Chem., 1979, 44, 1074).

Ketones 77 (a=1; b=1; c=0; d=3) can be prepared by cyclization of an appropriate 3-(4-oxocyclohex-2-en-1-yl)propanamide followed by amide reduction (A. I. Meyers and D. Berney, J. Org. Chem. 1989, 54, 4673) or by reaction of but-3-en-2-one with an appropriate 1,4,5,6-tetrahydropyridine derivative (E. Vazquez et al., Tetrahedron Asymm., 2001, 12, 2099). Ketones 77 wherein a=0 can, in general, be transformed into ketones 77 wherein a=1 by means of 1,2-carbonyl transposition methods, such as those described by M. Ogata et al., Eur. J. Med. Chem. 1991, 26, 889; W. E. Fristad, T. R. Bailey and L. A. Paquette, J. Org. Chem. 1978, 43, 1620; J. A. Marshall and H. Roebke, J. Org. Chem. 1969, 34, 4188; Y. Tsuda ad S. Hosoi, Chem. Pharm. Bull. 1985, 33, 1745; and T. Nakai and T. Mimura, Tetrahedron Lett. 1979, 531.

Many of the alkylating agents R⁵-X (2), aldehydes and ketones RC(═O)R′ (9) and acylating agents RC(═O)X (21) used to install the R⁵ substituent into the compounds of Formula (Ia) and Formula (Ib), for example as shown in Schemes 1, 2 and 12 are commercially available or are well known in the art of organic chemistry, and methods for their preparation are well known and well exemplified. Such alkylating agents, aldehydes and ketones, acylating agents, and amines which have not been previously reported can be prepared using methods reported for the preparation of closely analogous compounds, and many other methods well known in the art. Such methods are reviewed in many well-known reference works, for example R. C. Larock, Comprehensive Organic Transformations, VCH, 1989; A. Katritzky et al. (series editors), Comprehensive Organic Functional Group Transformations, Pergamon, 1995; and B. Trost and I. Fleming (series editors), Comprehensive Organic Synthesis, Pergamon, 1991. Methods for producing these compounds using such known methods will be obvious to one skilled in the art.

EXAMPLES Example 1 Part A: Preparation of 3-bromo-5-nitrobenzoic acid

A solution of 3-nitrobenzoic acid (16.7 g, 100 mmol) in trifluoroacetic acid (50 mL) and sulfuric acid (20 mL) was stirred at 50° C., and N-bromosuccinimide (26.7 g, 150 mmol) was added in three portions over 3 hours. The mixture was stirred for 16 hours and then cooled to room temperature. The mixture was then poured into ice water (200 mL) and extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was recrystallized from dichloromethane to provide a white solid (17.7 g, 72%). ¹H NMR (300 MHz, DMSO-d₆) δ13.8 (bs, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.37 (s, 1H).

Part B: Preparation of N-methyl-3-bromo-5-nitrobenzamide

A suspension of 3-bromo-5-nitrobenzoic acid (7.10 g, 28.9 mmol) in dichloromethane (50 mL) was treated with oxalyl chloride (5.04 mL, 57.7 mmol) and a few drops of N,N-dimethylformamide, producing gas evolution. After 2 hours, the mixture was concentrated to give an oil, which was dissolved in tetrahydrofuran and added dropwise to a stirred solution of methylamine in tetrahydrofuran (2.0 M, 28.9 mL, 57.7 mmol) at 0° C. After stirring overnight, the mixture was treated with water, ethyl acetate and 0.2 N aqueous hydrochloric acid. The layers were separated after mixing, and the organic phase was washed with 0.2 N aqueous hydrochloric acid, then with saturated aqueous sodium chloride. The solution was dried over sodium sulfate and concentrated under vacuum to provide a yellow solid (7.0 g, 94%). ¹H NMR (300 MHz, DMSO-d₆) δ9.92 (m, 1H), 8.64 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 2.81 (d, J=7 Hz, 3H).

Part C: Preparation of 5-(3-bromo-5-nitrophenyl)-1-methyl-1H-tetrazole

A suspension of N-methyl-3-bromo-5-nitrobenzamide (23.2 g, 90 mmol) in acetonitrile (200 mL) was treated with sodium azide (5.82 g, 90 mmol) and cooled to 0° C.

Trifluoromethanesulfonic anhydride (15.1 mL, 90 mmol) was added dropwise very slowly. After the mixture was stirred for 4 hours, saturated aqueous sodium hydrogen carbonate was added and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate and the organic phase was washed twice with saturated aqueous sodium hydrogen carbonate, once with saturated sodium chloride, and dried over magnesium sulfate. Concentration provided a dark amber oil which was stirred in ethyl acetate (25 mL) to provide a precipitate, which was isolated by filtration and dried to provide a tan solid (10.5 g). The filtrate was purified by silica gel chromatography, eluting with dichloromethane, to provide additional solid (9.0 g, 76% total). ¹H NMR (300 MHz, CDCl₃) δ8.60 (s, 1H), 8.55 (s, 1H), 8.32 (s, 1H), 7.26 (s, 1H), 4.29 (s, 3H).

Part D: Preparation of 1-methyl-5-(3-nitro-5-vinylphenyl)-1H-tetrazole

A mixture of 5-(3-bromo-5-nitrophenyl)-1-methyl-1H-tetrazole (19.50 g, 68.6 mmol), tributylvinyl tin (20.06 mL, 68.6 mmol) and tetrakis(triphenylphosphine)palladium (1.59 g, 1.37 mmol) in toluene was heated at reflux for 2 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a step gradient from dichloromethane to 50% ethyl acetate in dichloromethane, to provide a solid (22.0 g) containing a tributyltin-containing impurity. ¹H NMR (300 MHz, CDCl₃) δ8.49 (d, J=7 Hz, 2H), 8.19 (s, 1H), 6.86 (m, 1H), 6.05 (d, J=15 Hz, 1H), 5.60 (d, J=7 Hz, 1H), 4.28 (s, 3H).

Part E: Preparation of 3-ethyl-5-(1-methyl-1H-tetrazole-5-yl)aniline

A mixture of impure 1-methyl-5-(3-nitro-5-vinylphenyl)-1H-tetrazole (17.0 g) and palladium hydroxide on charcoal (3.0 g) in methanol (50 mL) was shaken under a hydrogen atmosphere (50 psig) for 4 hours. The mixture was filtered and the filtrate was concentrated under vacuum to provide an amber solid (14.3 g). ¹H NMR (300 MHz, CDCl₃) δ6.90 (s, 1H), 6.87 (s, 1H), 6.73 (s, 1H), 4.16 (s, 3H), 3.95 (bs, 2H), 2.65 (q, J=7 Hz, 2H), 1.22 (t, J=7 Hz, 3H).

Part F: Preparation of [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester

A solution of 3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)aniline (3.83 g, 19 mmol) in tetrahydrofuran was treated with 2,6-lutidine (2.17 mL, 19 mmol) and cooled to 0° C. A solution of phenyl chloroformate (2.36 mL, 19 mmol) in tetrahydrofuran was added dropwise. The mixture was stirred for 1 hour, then diluted with ethyl acetate and 0.1 N aqueous hydrochloric acid. The separated organic phase was washed twice with 0.1 N aqueous hydrochloric acid, then with saturated aqueous sodium chloride. The solution was dried over magnesium sulfate and concentrated under vacuum to provide a tan solid (6.00 g, quantitative). ¹H NMR (300 MHz, CDCl₃) δ7.86 (s, 1H), 7.5-7.3 (m, 5H), 7.3-7.1 (m, 3H), 4.17 (s, 3H), 2.71 (q, J=7 Hz, 2H), 1.27 (t, J=7 Hz, 3H).

Part G: Preparation of N-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-[(3aRS,4RS,6aSR)-2-trityloctahydrocyclo-penta[c]pyrrol-4-yl]urea

A mixture of (3aR,4R,6aS)-2-trityloctahydrocyclopenta[c]pyrrol-4-amine (prepared following the procedures of Patent publication EP 0 359 172 A1; 250 mg, 678 μmol), [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (219 mg, 678 μmol), triethylamine (189 μL, 1.36 mmol), acetonitrile (3 mL) and N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 18.5 hours. The mixture was concentrated under vacuum, and the residue was dissolved in ethyl acetate. The solution was washed with 1.0 N aqueous sodium hydroxide, and the organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with 40% ethyl acetate/hexane, to provide a white solid (353 mg, 87%). ¹H NMR (300 MHz, CDCl₃) δ8.04 (s, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.46 (d, J=7 Hz, 6H), 7.18 (t, J=7 Hz, 6H), 7.07 (t, J=7 Hz, 3H), 6.97 (s, 1H), 6.11 (d, J=7 Hz, 1H), 4.04 (s, 3H), 2.74 (m, 1H), 2.6-2.4 (m, 4H), 2.4-2.1 (m, 3H), 1.91 (m, 1H), 1.8-1.7 (m, 3H), 1.58 (m, 1H), 1.12 (t, J=7 Hz, 3H).

Part H: Preparation of N-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-[(3aRS,4RS,6aSR)-octahydrocyclopenta[c]-pyrrol-4-yl]urea

N-[3-Ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-[(3aRS,4RS,6aSR)-2-trityloctahydrocyclo-penta[c]pyrrol-4-yl]urea (310 mg, 518 μmol) was dissolved in trifluoroacetic acid (5 mL) to provide a bright yellow solution. This was treated dropwise with water (5 mL) to provide a pale yellow slurry. After 2 hours, the mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and 1.0 N aqueous hydrochloric acid. The aqueous phase was washed with additional ethyl acetate, and then made strongly basic with 50% aqueous sodium hydroxide. The resulting mixture was extracted three times with ethyl acetate, and these organic phases were combined, dried over sodium sulfate, and concentrated under vacuum to provide a white glass (167 mg, 90%). NMR (300 MHz, CDCl₃) δ7.71 (s, 1H), 7.69 (s, 1H), 7.29 (s, 1H), 7.18 (s, 1H), 6.49 (d, J=8 Hz, 1H), 4.27 (m, 1H), 4.20 (s, 3H), 2.97 (m, 2H), 2.8-2.6 (m, 6H), 1.90 (m, 1H), 1.70 (m, 2H), 1.36 (m, 1H), 1.24 (t, J=7 Hz, 3H).

Part I: Preparation of toluene-4-sulfonic acid 2-(4-fluorophenyl)ethyl ester

A solution of 2-(4-fluorophenyl)ethanol(10.0 g, 71.3 mmol) in pyridine (100 mL) was stirred at −5° C. and treated with 4-toluenesulfonyl chloride (14.95 g, 78.4 mmol). After 3 hours, water (10 mL) was added slowly, followed by dilution with ice water and extraction with chloroform. The organic phase was washed with cold 0.5 M aqueous sulfuric acid, then with water, then with saturated aqueous sodium chloride, and was dried over sodium sulfate. Concentration under vacuum provided a pale orange oil containing residual pyridine. Further concentration under vacuum provided an oil (17.74 g) containing about 10% by weight of residual alcohol. A portion was purified by flash chromatography, eluting with 20% ethyl acetate in hexane, to provide a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ7.70 (d, J=8 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 7.07 (m, 2H), 6.94 (t, J=9 Hz, 2H), 4.20 (t, J=7 Hz, 2H), 2.94 (t, J=7 Hz, 2H), 2.45 (s, 3H).

Part J: Preparation of N-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-{(3aRS,4RS,6aSR)-2-[2-(4-fluorophenyl)-ethyl]octahydrocyclopenta[c]pyrrol-4-yl}urea

A mixture of N-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-N′-[(3aRS,4RS,6aSR)-octahydrocyclopenta[c]-pyrrol-4-yl]urea (60 mg, 169 μmol), toluene-4-sulfonic acid 2-(4-fluorophenyl)ethyl ester (55 mg, 169 μmol), potassium carbonate (24 mg, 169 μmol) and acetonitrile (1 mL) was heated to reflux. After 15.5 hours, the mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography, eluting with 2% methanol/dichloromethane containing 0.2% aqueous ammonia, to provide a white glass (61 mg, 76%). ¹H NMR (300 MHz, CDCl₃) δ7.75 (s, 1H), 7.27 (s, 2H), 7.23 (m, 2H), 7.08 (s, 1H), 7.04 (m, 2H), 6.24 (broad s, 1H), 4.23 (broad s, 1H), 4.19 (s, 3H), 3.0-2.6 (m, 10H), 2.3-2.1 (m, 2H), 2.05 (m, 1H), 1.8-1.5 (m, 4H), 1.35 (m, 1H), 1.27 (t, J=7 Hz, 3H). Mass spec (ES⁺) m/z 478.3 (M+H⁺, 100%)

Example 2 Part A: Preparation of hexa-3,5-dien-1-yl 4-methylbenzenesulfonate

A solution of ethyl hexa-3,5-dienoate (4.0 g, 28.6 mmol) in dry tetrahydrofuran (200 mL) was treated with a solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 28.6 mL, 28.6 mmol). The mixture was stirred at room temperature for 2 hours, and then quenched with water. The mixture was acidified with 1.0 N aqueous hydrochloric acid and extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated to a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ6.4-6.1 (m, 2H), 5.67 (m, 1H), 5.13 (d, J=17 Hz, 1H), 5.00 (d, J=11 Hz, 1H), 3.66 (t, J=6.6 Hz, 2H), 2.34 (q, J=6.6 Hz, 2H), 2.13 (broad s, 1H). The oil was dissolved in dichloromethane, cooled to 0° C. and treated with pyridine (10 mL) and p-toluenesulfonyl chloride (5.72 g, 30 mmol). The mixture was stirred for one hour, then warmed to room temperature and stirred for 3 hours. The mixture was then concentrated, and the residue was dissolved in ethyl acetate, washed sequentially with water, 1.0 N aqueous hydrochloric acid, 1.0 N aqueous sodium hydroxide, and saturated aqueous sodium chloride, then was dried over magnesium sulfate and concentrated to provide a yellow oil. This yellow oil was purified by flash column chromatography, eluting with 10% ethyl acetate/hexane, to give a colorless oil (3.84 g, 53%). ¹H NMR (300 MHz, CDCl₃) δ7.78 (d, J=8 Hz, 2H), 7.33 (d, J=8 Hz, 2H), 6.22 (td, J=17, 10 Hz, 1H), 6.04 (dd, J=11, 10 Hz, 1H), 5.10 (d, J=17 Hz, 1H), 5.02 (d, J=10 Hz, 1H), 4.05 (t, J=7 Hz, 2H), 2.44 (s+m, 5H).

Part B: Preparation of N-benzylhexa-3,5-dien-1-amine

A solution of hexa-3,5-dien-1-yl 4-methylbenzenesulfonate (1.90 g, 7.53 mmol) and triethylamine (1.39 mL, 10.0 mmol) in acetonitrile (70 mL) was treated with benzylamine (2.45 mL, 22.5 mmol), and the mixture was stirred at room temperature for 16 hours. The solution was then heated to reflux for 3 hours, cooled, and treated with 1.0 N aqueous sodium hydroxide. The mixture was extracted three times with ethyl acetate. (A portion of the extracts were lost due to spillage). The combined organic phases were dried over magnesium sulfate and concentrated to provide a pale yellow oil. The yellow oil was purified by radial thin-layer chromatography, eluting with 25% ethyl acetate/hexane, to provide a colorless oil (628 mg, 45%). ¹H NMR (300 MHz, CDCl₃) δ7.32 (m, 4H), 7.26 (m, 1H), 6.32 (td, J=17, 10 Hz, 1H), 6.12 (dd, J=15, 10 Hz, 1H), 5.68 (td, J=15, 7 Hz, 1H), 5.12 (d, J=17 Hz, 1H), 5.00 (d, J=10 Hz, 1H), 3.80 (s, 2H), 2.71 (t, J=7 Hz, 2H), 2.32 (q, J=7 Hz, 2H), 1.52 (broad s, 1H). Mass spec (ES+) m/z 188.4 (M+H⁺, 100%).

Part C: Preparation of ethyl (4aRS,8SR,8aSR)-2-benzyl-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-carboxylate

A solution of N-benzylhexa-3,5-dien-1-amine (338 mg, 1.81 mmol) and triethylamine (0.378 mL, 2.72 mmol) in acetonitrile (15 mL) was treated with ethyl 4-bromobut-2-enoate (0.249 mL, 1.81 mmol). The mixture was stirred at room temperature for 72 hours, then heated to reflux for 6 hours. The mixture was cooled to room temperature and treated with water (15 mL), then extracted with ethyl acetate (3×15 mL). The combined organic phases were dried over magnesium sulfate and concentrated to provide a pale yellow oil. The pale yellow oil was purified by radial thin-layer chromatography, eluting with 10% ethyl acetate/hexane, to provide an oil (165 mg, 30%). ¹H NMR (300 MHz, CDCl₃) δ7.4-7.2 (m, 5H), 5.62 (m, 2H), 4.1-3.9 (m, 2H), 3.6-3.3 (m, 2H), 2.95 (m, 1H), 2.65 (m, 2H), 2.3-2.1 (m, 6H), 1.78 (m, 1H), 1.57 (m, 1H), 1.19 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 300.3 (M+H⁺, 100%).

Part D: Preparation of ethyl (4aSR,8SR,8aSR)-decahydroisoquinoline-8-carboxylate

A solution of ethyl (4aRS,8SR,8aSR)-2-benzyl-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-carboxylate (440 mg, 1.47 mmol) in methanol (10 mL) was treated with 10% palladium on charcoal (20 mg) and stirred for 16 hours under an atmosphere of hydrogen. The mixture was filtered, and the filtrate was concentrated to provide a colorless oil (305 mg, 98%). ¹H NMR (300 MHz, CDCl₃) δ4.09 (q, J=7 Hz, 2H), 3.07 (m, 1H), 2.94 (dd, J=12, 4 Hz, 1H), 2.60 (m, 2H), 2.25 (J=12, 11 Hz, 1H), 2.0-1.7 (m, 3H), 1.6-1.2 (m, 6H), 1.91 (t, J=7 Hz, 3H), 1.10 (m, 2H). Mass spec (ES+) m/z 212.4 (M+H⁺, 100%).

Part E: Preparation of ethyl (4aSR,8SR,8aSR)-2-[3-(4-fluorophenyl)propanoyl]decahydroisoquinoline-8-carboxylate

A solution of ethyl (4aSR,8SR,8aSR)-decahydroisoquinoline-8-carboxylate (273 mg, 1.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (309 mg, 1.61 mmol) in dichloromethane (10 mL) was treated with 3-(4-fluorophenyl)propanoic acid (271 m, 1.61 mmol). The mixture was stirred at room temperature for 4 hours, and then treated with 1.0 N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (3×5 mL), and the combined organic phases were washed with 1.0 N aqueous sodium hydroxide, dried over magnesium sulfate and concentrated to provide a residue. The residue was purified by radial thin layer chromatography, eluting with 33% ethyl acetate/hexane, to provide a colorless oil (385 mg, 82%).

¹H NMR (300 MHz, CDCl₃) δ7.15 (m, 2H), 6.91 (m, 2H), 4.62 (m, 1H), 4.10 (m, 2H), 3.74 (m, 1H), 2.89 (t, J=8 Hz, 2H), 2.6-2.4 (m, 3H), 2.2-1.8 (m, 2H), 1.77 (m, 1H), 1.7-0.9 (m, 9H).

Part F: Preparation of (4aSR,8SR,8aSR)-2-[3-(4-fluorophenyl)propanoyl]decahydroisoquinoline-8-carboxylic acid

A solution of ethyl (4aSR,8SR,8aSR)-2-[3-(4-fluorophenyl)propanoyl]decahydroisoquinoline-8-carboxylate (385 mg, 1.07 mmol) in tetrahydrofuran (5 mL) was added to a solution of potassium hydroxide (168 mg, 3.0 mmol) in water (5 mL). The resulting solution was stirred at room temperature for 16 hours. Additional potassium hydroxide (385 mg, 1.07 mmol) dissolved in methanol (5 mL) was added, and stirring was continued for an additional 5 hours. The mixture was treated with concentrated aqueous hydrochloric acid until the pH was about 1. The mixture was concentrated to a volume of about 5 mL and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated to provide a white solid (350 mg, 98%). ¹H NMR (300 MHz, CDCl₃) δ7.11 (m, 2H), 6.90 (m, 2H), 4.66 (m, 1H), 3.80 (m, 1H), 2.85 (m, 2H), 2.7-2.4 (m, 3H), 2.1-1.9 (m, 2H), 1.80 (m, 1H), 1.7-0.9 (m, 9H). Mass spec (ES+) m/z 334.2 (M+H⁺, 100%).

Part G: Preparation of tert-butyl {(4aSR,8SR,8aRS)-2-[3-(4-fluorophenyl)propanoyl]decahydroisoquinolin-8-yl}carbamate

A solution of ethyl (4aSR,8SR,8aSR)-2-[3-(4-fluorophenyl)propanoyl]decahydroisoquinoline-8-carboxylic acid (345 mg, 1.04 mmol) and triethylamine (159 μL, 1.14 mmol) in tert-butanol (20 mL) was stirred with 4 Å molecular sieves. The mixture was treated with diphenylphosphoryl azide (245 μL, 1.14 mmol) and stirred for 30 minutes at room temperature. The mixture was then heated to reflux for 4 hours, then cooled to room temperature and concentrated under vacuum to provide a residue. The residue was dissolved in ethyl acetate, and the solution was washed with 1.0 N aqueous sodium hydroxide, then with brine, and dried over magnesium sulfate and concentrated to provide a residue. The residue was purified by radial thin layer chromatography, eluting with 50% ethyl acetate/hexane, to provide a white solid (221 mg, 53%), which was a mixture of carbamate rotamers. ¹H NMR (300 MHz, CDCl₃) δ7.15 (m, 2H), 6.95 (m, 2H), 4.80+4.66 (2d, J=14 Hz, 1H), 4.50+4.25 (2d, J=9 Hz, 1H), 3.80 (m, 1H), 3.24 (m, 1H), 2.91 (m, 2H), 2.7-2.4 (m, 3H), 2.3-1.9 (m, 2H), 1.73 (d, J=14 Hz, 1H), 1.60 (m, 2H), 1.42+1.37 (2s, 9H), 1.3-0.7 (m, 6H). Mass spec (ES+) m/z 405.3 (M+H⁺, 100%).

Part H: Preparation of (4aSR,8SR,8aRS)-2-[3-(4-fluorophenyl)propyl]decahydroisoquinolin-8-amine

A solution of tert-butyl {(4aSR,8SR,8aRS)-2-[3-(4-fluorophenyl)propanoyl]decahydroisoquinolin-8-yl}carbamate (220 mg, 544 μmol) in tetrahydrofuran (5 mL) was treated with a solution of borane in tetrahydrofuran (1.0 M; 1.0 mL, 1.0 mmol) and the mixture was heated at reflux for 3 hours. The mixture was cooled and treated with 1.0 N aqueous hydrochloric acid and then heated at reflux for 2 hours. The mixture was cooled again to room temperature and concentrated to provide a white solid. The white solid was partitioned between ethyl acetate and 2.0 N aqueous sodium hydroxide. The organic phase was separated, dried over magnesium sulfate and concentrated to provide a colorless oil (151 mg, 95%). ¹H NMR (300 MHz, CDCl₃) δ7.05 (m, 2H), 6.87 (m, 2H), 3.57 (t, J=6 Hz, 2H), 3.51 (t, J=7 Hz, 2H), 3.20 (m, 1H), 2.86 (m, 1H), 2.51 (m, 2H), 2.44 (broad s, 2H), 2.4-2.2 (m, 2H), 1.8-1.4 (m, 7H), 1.3-0.8 (m, 3H). Mass spec (ES+) m/z 291.3 (M+H⁺, 100%).

Part I: Preparation of N-(3-acetylphenyl)-N′-{(4aSR,8SR,8aRS)-2-[3-(4-fluorophenyl)propyl]-decahydroisoquinolin-8-yl}urea

A solution of (4aSR,8SR,8aRS)-2-[3-(4-fluorophenyl)propyl]decahydroisoquinolin-8-amine (15 mg, 50 μmol) in tetrahydrofuran (1 mL) was treated with 3-acetylphenylisocyanate (8.3 mg, 50 mmol). The mixture was stirred for 30 minutes, then treated with methanol (0.5 mL). The mixture was concentrated under vacuum to provide a residue. The residue was purified by flash column chromatography, eluting with 5% triethylamine/ethyl acetate, to provide a white solid (11.4 mg, 49%). ¹H NMR (300 MHz, CDCl₃) δ7.80 (s, 1H), 7.78 (d, J=8 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J=8 Hz, 1H), 7.29 (t, J=8 Hz, 1H), 7.00 (m, 2H), 6.83 (m, 2H), 5.16 (d, J=10 Hz, 1H), 3.61 (m, 1H), 3.42 (m, 1H), 3.08 (m, 1H), 2.94 (m, 1H), 2.53 (s, 3H), 2.47 (t, J=8 Hz, 2H), 2.4-2.2 (m, 2H), 1.9-1.5 (m, 8H), 1.4-0.8 (m, 5H). Mass spec (ES+) m/z 452.3 (M+H⁺, 100%).

Example 5 Part A: Preparation of t-butyl 3-oxo-1-piperidinecarboxylate

To a stirred solution of N-benzyl-3-piperidone hydrochloride hydrate (4.2 g, 18.6 mmol) and 10% palladium on carbon (0.8 g) in degassed methanol (200 mL) was added hydrogen gas to 55 psi. The reaction mixture was stirred for 16 hr and then filtered through a pad of celite. The celite was washed with methanol (200 mL). The filtrates were combined and concentrated in vacuo to a colorless oil. The oil was dissolved in tetrahydrofuran (200 mL) and then treated with di-t-butyl-dicarbonate (5.27 g, 24.1 mmol) and a saturated aqueous sodium bicarbonate solution (50 mL). The reaction was stirred for 4 hr and then concentrated in vacuo to a white solid. The solid was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with 1N sodium hydroxide and brine, dried over Na₂SO₄, and evaporated in vacuo to a colorless oil. The oil was purified by flash chromatography (silica gel, hexane:ethyl acetate 3:1) to yield 2.93 g of a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 3.99 (s, 2H), 3.58 (t, J=6, 2H), 2.46 (t, J=6, 2H), 1.97 (p, J=6, 2H), 1.45 (s, 9H).

Part B: Preparation of t-butyl 3-(4-fluorobenzylidene)-1-piperidinecarboxylate

To a stirred solution of (4-fluorophenylmethyl)triphenylphosphonium chloride (17.68 g, 43.5 mmol) in dry tetrahydrofuran (60 mL) at −78° C. was added 2.5 M n-butyllithium in hexane (14.6 mL, 36.5 mmol). The reaction was warmed to 0° C. for 1 hr. After tis time, t-butyl 3-oxo-1-piperidinecarboxylate (3.46 g, 17.4 mmol) in tetrahydrofuran (60 mL) was added. The mixture was stirred at room temperature for 1 hr and then heated to reflux for 16 hr. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride. The reaction was extracted with ethyl acetate three times (100 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, hexane:ethyl acetate 9:1) to yield 3.82 g of a mixture of E and Z isomers as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.22-7.14 (m, 2H), 7.04-6.98 (m, 2H), 6.36 (s, 0.33H), 6.28 (s, 0.67H), 4.14 (s, 1.34H), 4.00 (s, 0.66H) 3.50 (t, J=5, 2H), 2.47 (t, J=5, 0.66H), 2.39 (t, J=5, 1.34H), 1.75-1.68 (m, 1.34H), 1.65-1.57 (m, 0.66H), 1.48 (s, 9H).

Part C: Preparation of t-butyl (±)-3-(4-fluorobenzyl)-1-piperidinecarboxylate

To a stirred solution of the t-Butyl 3-(4-fluorobenzylidene)-1-piperidinecarboxylate (3.82 g, 13.1 mmol) and 10% palladium on carbon (0.76 g) in degassed methanol (200 mL) was added hydrogen gas to 55 psi. The reaction was stirred for 16 h and then filtered through a pad of celite. The celite was washed with methanol (200 mL). The filtrates were combined and concentration in vacuo to yield 2.76 g of a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.12-7.07 (m, 2H), 6.98-6.93 (m, 2H), 3.89 (dt, J=13, J′=4, 1H), 3.84-3.74 (m, 1H), 2.57-2.43 (m, 4H), 1.75-1.60 (m, 4H), 1.42 (s, 9H), 1.15-1.09 (m, 1H).

Part D: Preparation of (3S)-3-(4-fluorobenzyl)piperidine, mandelic acid salt

N-BOC-3-(4-fluorobenzyl)piperidine (5 g) was dissolved in 30 mL of 4N hydrochloric acid in dioxane. Some initial gas evolution occurred which eventually subsided. After one hour, the mixture was neutralized with aqueous sodium carbonate, and the dioxane was evaporated off to provide a residue. The residue was extracted with ether. The combined ether extracts were dried over magnesium sulfate and the ether was evaporated off to give 2.6 g of the free amine as a discolored oil. This crude material was used to make the diastereomeric salts.

Resolution of 3-(4-fluorobenzyl)piperidine

The crude racemic 3-(4-fluorobenzyl)piperidine (2.0 g) was dissolved in 25 mL acetonitrile and heated to reflux. The solution was hazy. To this was added 1.56 g (1 equivalent) of (R)-(−) mandelic acid dissolved in 15 mL acetonitrile. Some initial precipitation occurred when the cooler solution was added but it redissolved when refluxing resumed. The heat was turned off and small amounts of enantiomerically pure salt were added as the temperature dropped. At first the seed crystals dissolved, but when the temperature dropped to 75° C., they remained suspended in the stirred solution. After a few more degrees of cooling, crystal growth was obvious. Cooling was continued at the rate of 1 degree/min. At 50° C., the solution was filtered to recover 0.9 g of salt, which melted at 164° C. It was recrystallized from acetonitrile twice to give (S)-(+)-3-(4-fluorobenzyl)piperidine mandelic acid salt in 98% enantiomeric excess, mp 168-171° C.

Part E: Preparation of (3aRS,4RS,6aSR)-4-[(3S)-3-(4-fluorobenzyl)piperidin-1-yl]-2-trityloctahydrocyclopenta[c]pyrrole

A mixture of (S)-(+)-3-(4-fluorobenzyl)piperidine mandelic acid salt (2.23 g, 6.5 mmol), ethyl acetate (20 mL) and 1.0 N aqueous sodium hydroxide (20 mL) was stirred at room temperature until dissolution. The organic phase was removed, and the aqueous phase was extracted with additional ethyl acetate. The combined organic phases were dried over sodium sulfate, and a portion was concentrated to provide an oil (525 mg, 2.72 mmol). The oil was dissolved in 1,2-dichloroethane (15 mL) and treated with (3aRS,6aSR)-2-tritylhexahydrocyclopenta[c]pyrrol-4(1H)-one (prepared following the procedures of M. Ogata et al., Eur. J. Med. Chem. 1991, 26, 889; 1.33 g, 3.6 mmol), acetic acid (208 μL, 3.6 mmol), and sodium triacetoxyborohydride (921 mg, 4.3 mmol). The mixture was stirred at room temperature for 69 hours, and then treated with 1.0 N aqueous sodium hydroxide (25 mL). The resulting mixture was extracted three times with ether. The combined organic extracts were dried over sodium sulfate and concentrated to provide a glass. The glass was purified by flash column chromatography, eluting with chloroform, then with 2% isopropanol/chloroform, then with 3% isopropanol/chloroform. The (bicyclic ketone) starting material (412 mg, 31%) was recovered, along with the desired product as a glass (1.09 g, 73%). ¹H NMR (300 MHz, CDCl₃) δ 7.50 (d, J=7 Hz, 6H), 7.25 (m, 6H), 7.14 (m, 3H), 7.0-6.8 (m, 4H), 3.0-2.8 (m, 2H), 2.7-2.2 (m, 8H), 2.1-1.5 (11H), 1.0 (m, 1H).

Part F: Preparation of (3aRS,4RS,6aSR)-4-[(3S)-3-(4-fluorobenzyl)piperidin-1-yl]octahydrocyclopenta[c]pyrrole

(3aRS,4RS,6aSR)-4-[(3S)-3-(4-fluorobenzyl)piperidin-1-yl]-2-trityloctahydrocyclo-penta[c]pyrrole (500 mg, 918 μmol) was dissolved in trifluoroacetic acid (4 mL) to form a dark orange-yellow solution. Water (5 mL) was added dropwise to form a dense slurry, lighter in color. After 40 minutes, the mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate and extracted with 1.0 N aqueous hydrochloric acid. The aqueous phase was washed with ethyl acetate, and then made strongly basic by the addition of 50% aqueous sodium hydroxide. The resulting mixture was extracted several times with ether, and the combined ether phases were dried over sodium sulfate and concentrated, yielding a gum (263 mg, 95%), which was used without further purification. ¹H NMR (300 MHz, CDCl₃) δ 7.08 (m, 2H), 6.95 (m, 2H), 3.14 (m, 1H), 3.0-2.6 (m, 4H), 2.6-2.3 (m, 7H), 2.0-1.2 (m, 9H), 0.93 (m, 1H). Mass spec (CH₄-CI) m/z 303.2 (M+H⁺, 100%).

Part G: Preparation of (3aRS,4RS,6aSR)-N-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-4-[(3S)-3-(4-fluorobenzyl)piperidin-1-yl]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide

A mixture of (3aRS,4RS,6aSR)-4-[(3S)-3-(4-fluorobenzyl)piperidin-1-yl]octahydrocyclopenta[c]pyrrole (53 mg, 175 μmol), [3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (56 mg, 175 μmol), triethylamine (49 μL, 350 μmol) and acetonitrile (2 mL) was stirred at room temperature. After 18 hours, the mixture was concentrated to provide a residue. The residue was dissolved in ethyl acetate. The solution was washed with 1.0 N aqueous sodium hydroxide, and was dried over sodium sulfate and concentrated to provide a residue. The residue was purified by flash column chromatography, eluting with 2% methanol/dichloromethane containing 0.2% aqueous ammonia, to provide a tan glass (56 mg, 75%). ¹H NMR (300 MHz, CDCl₃) δ7.83 (s, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 7.09 (m, 2H), 6.96 (m, 2H), 6.52 (broad s, 1H), 4.22 (s, 3H), 3.61 (m, 2H), 3.5-3.2 (m, 2H), 3.0-2.6 (m, 6H), 2.6-2.4 (m, 3H), 2.0-1.5 (m, 10H), 1.27 (m, 3H), 0.93 (m, 1H). Mass spec (ES⁺) m/z 532.4 (M+H⁺, 100%)

Representative compounds prepared by the methods disclosed above are listed in Tables 1 and 2.

TABLE 1

Ex- Mass am- spec, ple a b c d R³ R⁵ (M + H)⁺ 1 0 1 1 1 3-ethyl-5-(1- 4-F—C₆H₄— 478 methyl-tetrazol-5- (CH₂)₂— yl)-C₆H₄ 2 0 2 1 2 3-acetyl-C₆H₄ 4-F—C₆H₄— 452 (CH₂)₃— 3 0 2 1 2 4-F—C₆H₄— 4-F—C₆H₄— 428 (CH₂)₃— 4 0 1 1 1 3-ethyl-5-(1- 4-F—C₆H₄— 492 methyl-tetrazol-5- (CH₂)₃— yl)-C₆H₄

TABLE 2

wherein a is 0; b, c and d are 1 Ex- Mass am- spec, ple R³ R⁵ R^(5a) (M + H)⁺ 5 3-ethyl-5-(1-methyl-tetrazol-5-yl)-C₆H₄

532 6 3-acetyl-C₆H₄

7 3-acetyl-5-(1-methyl-tetrazol-5-yl)-C₆H₄

8 3-ethyl-5-(1-methyl- (CH₂)₃—C₆H₄—4F CH₃ tetrazol-5-yl)-C₆H₄

Utility

The utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assays for CCR-2 and CCR-3 ligand binding, as disclosed by Ponath et al., J. Exp. Med., 183, 2437-2448 (1996) and Uguccioni et al., J. Clin. Invest., 100, 1137-1143 (1997). Cell lines for expressing the receptor of interest include those naturally expressing the chemokine receptor, such as EOL-3 or THP-1, those induced to express the chemokine receptor by the addition of chemical or protein agents, such as HL-60 or AML14.3D10 cells treated with, for example, butyric acid with interleukin-5 present, or a cell engineered to express a recombinant chemokine receptor, such as CHO or HEK-293. Finally, blood or tissue cells, for example human peripheral blood eosinophils, isolated using methods as described by Hansel et al., J. Immunol. Methods, 145, 105-110 (1991), can be utilized in such assays.

The utility of the compounds in accordance with the present invention as inhibitors of the migration of eosinophils or cell lines expressing the chemokine receptors may be demonstrated by methodology known in the art, such as the intracellular calcium measurement (disclosed by Bacon et al., Brit. J. Pharmacol., 95, 966-974 (1988)). In particular, the compounds of the present invention have activity in inhibition of the migration of eosinophils in the aforementioned assays. As used herein, “activity” is intended to mean a compound demonstrating an IC50 of 10 μM or lower in concentration when measured in the aforementioned assays. Such a result is indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity. An intracellular calcium measurement protocol is described below.

Intracellular Ca²⁺ Measurement

Cells (8×10⁵/mL) were loaded with 4 μM Fluo-3 AM (Molecular Probes, Eugene. Oreg.) in calcium-free PBS containing 0.1% BSA, 1% FBS, 20 mM HEPES, 5 mM glucose and 2.5 mM probenecid) for 60 minutes at 37° C. in the dark. After two washes in buffer (PBS with 0.1% BSA, 20 mM HEPES, 5 mM glucose and 2.5 mM probenecid), cells (2×10⁶/mL) were resuspended in RPMI containing 0.1% BSA, 20 mM HEPES and 2.5 mM probenecid and plated in 96-well black, clear-bottomed plates (# 3603, Corning, Acton, Mass.), previously coated with poly-D-lysine, at 2×10⁵/well. Individual plates were inserted in a FLIPR (Molecular Devices, Sunnyvale, Calif.). Compound or vehicle (50 μL) was added robotically and incubated for 5 minutes at room temperature, then eotaxin (50 μL) was added for a final concentration of 10 nM. The eotaxin-dependent increase in fluorescence over baseline was recorded in duplicate wells.

The utility of the compounds in accordance with the present invention as inhibitors of the migration of eosinophils or cell lines expressing the chemokine receptors may be demonstrated by methodology known in the art, such as the chemotaxis assay disclosed by Bacon et al., Brit. J. Pharmacol., 95, 966-974 (1988). In particular, the compounds of the present invention have activity in inhibition of the migration of eosinophils in the aforementioned assays. As used herein, “activity” is intended to mean a compound demonstrating an IC50 of 10 μM or lower in concentration when measured in the aforementioned assays. Such a result is indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity. A human eosinophil chemotaxis assay protocol is described below.

Human Eosinophil Chemotaxis Assay

Neuroprobe MBA96 96-well chemotaxis chambers with Neuroprobe polyvinylpyrrolidone-free polycarbonate PFD5 5-micron filters in place are warmed in a 37° C. incubator prior to assay. Freshly isolated human eosinophils, isolated according to a method such as that described by Hansel et al. (1991), are suspended in RPMI 1640 with 0.1% bovine serum albumin at 1×10⁶ cells/ml and warmed in a 37° C. incubator prior to assay. A 20 nM solution of human eotaxin in RPMI 1640 with 0.1% bovine serum albumin is warmed in a 37° C. incubator prior to assay. The eosinophil suspension and the 20 nM eotaxin solution are each mixed 1:1 with prewarmed RPMI 1640 with 0.1% bovine serum albumin with or without a dilution of a test compound that is at two fold the desired final concentration. These mixtures are warmed in a 37° C. incubator prior to assay. The filter is separated from the prewarmed Neuroprobe chemotaxis chamber and the eotaxin/compound mixture is placed into a Polyfiltronics MPC 96 well plate that has been placed in the bottom part of the Neuro Probe chemotaxis chamber. The approximate volume is 370 microliters and there should be a positive meniscus after dispensing. The filter is replaced above the 96 well plate, the rubber gasket is attached to the bottom of the upper chamber, and the chamber assembled. A 200 μl volume of the cell suspension/compound mixture is added to the appropriate wells of the upper chamber. The upper chamber is covered with a plate sealer, and the assembled unit placed in a 37° C. incubator for 45 minutes. After incubation, the plate sealer is removed and all remaining cell suspension is aspirated off. The chamber is disassembled and, while holding the filter by the sides at a 90-degree angle, unmigrated cells are washed away using a gentle stream of phosphate buffered saline dispensed from a squirt bottle and then the filter wiped with a rubber tipped squeegee. The filter is allowed to completely dry and immersed completely in Wright Giemsa stain for 30-45 seconds. The filter is rinsed with distilled water for 7 minutes, rinsed once with water briefly, and allowed to dry. Migrated cells are enumerated by microscopy.

Mammalian chemokine receptors provide a target for interfering with or promoting immune cell function in a mammal, such as a human. Compounds that inhibit or promote chemokine receptor function are particularly useful for modulating immune cell function for therapeutic purposes. Accordingly, the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, infection by pathogenic microbes (which, by definition, includes viruses), as well as autoimmune pathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions of a mammalian chemokine receptor (e.g., a human chemokine receptor) may be administered to inhibit (i.e., reduce or prevent) inflammation or infectious disease. As a result, one or more inflammatory process, such as leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited. For example, eosinophilic infiltration to inflammatory sites (e.g., in asthma or allergic rhinitis) can be inhibited according to the present method. In particular, the compound of the following examples has activity in blocking the migration of cells expressing the CCR-3 receptor using the appropriate chemokines in the aforementioned assays. As used herein, “activity” is intended to mean a compound demonstrating an IC50 of 10 μM or lower in concentration when measured in the aforementioned assays. Such a result is also indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity.

Similarly, an instant compound which promotes one or more functions of the mammalian chemokine receptor (e.g., a human chemokine) as administered to stimulate (induce or enhance) an immune or inflammatory response, such as leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes. For example, eosinophils can be recruited to combat parasitic infections. In addition, treatment of the aforementioned inflammatory, allergic and autoimmune diseases can also be contemplated for an instant compound which promotes one or more functions of the mammalian chemokine receptor if one contemplates the delivery of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor internalization or the delivery of compound in a manner that results in the misdirection of the migration of cells.

In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals, including but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species. The subject treated in the methods above is a mammal, male or female, in whom modulation of chemokine receptor activity is desired. “Modulation” as used herein is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism.

Diseases or conditions of human or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-type hypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome due to the ingestion of contaminated tryptophan, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such as an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or organs. Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis. Infectious diseases or conditions of human or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treated with promoters of chemokine receptor function, include, but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS or other viral infections, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due to congenital deficiency in receptor function or other causes; and infections diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms); (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis); trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceral worms, visceral larva migraines (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larva migraines (Ancylostona braziliense, Ancylostoma caninum). The compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory, infectious and immunoregulatory disorders and diseases. In addition, treatment of the aforementioned inflammatory, allergic and autoimmune diseases can also be contemplated for promoters of chemokine receptor function if one contemplates the delivery of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor internalization or delivery of compound in a manner that results in the misdirection of the migration of cells.

In another aspect, the instant invention may be used to evaluate the putative specific agonists or antagonists of a G protein coupled receptor. The present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds that modulate the activity of chemokine receptors. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition or as a reference in an assay to compare its known activity to a compound with an unknown activity. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness. Specifically, such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving the aforementioned diseases. The compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors. In addition, one could utilize compounds of this invention to examine the specificity of G protein coupled receptors that are not thought to be chemokine receptors, either by serving as examples of compounds which do not bind or as structural variants of compounds active on these receptors which may help define specific sites of interaction.

Combined therapy to prevent and treat inflammatory, infectious and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities. For example, in the treatment or prevention of inflammation, the present compounds may be used in conjunction with an anti-inflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumor necrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal anti-inflammatory agent, a phosphodiesterase inhibitor, or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, interferon alpha and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine; and antitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that may be combined with a compound of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) integrin antagonists such as those for selectins, ICAMs and VLA-4; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (H1-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as b2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors of phosphodiesterase type IV (PDE-IV); (i) other antagonists of the chemokine receptors; (j) cholesterol lowering agents such as HMG-COA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvsatatin, and other statins), sequestrants (cholestyramine and colestipol), nicotonic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (k) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), a-glucosidase inhibitors (acarbose) and glitazones (troglitazone ad pioglitazone); (1) preparations of interferons (interferon alpha-2a, interferon-2B, interferon alpha-N3, interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m) antiviral compounds such as efavirenz, nevirapine, indinavir, ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) other compounds such as 5-aminosalicylic. acid and prodrugs thereof, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective doses of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

The compounds are administered to a mammal in a therapeutically effective amount. By “therapeutically effective amount” it is meant an amount of a compound of Formula Ia and/or Formula Ib that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenbusly, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula Ia and/or Formula Ib and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula Ia and/or Formula Ib, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula Ia and/or Formula Ib and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

While the invention has been described in detail and with reference to specific-embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. 

1. A compound of formula (Ia):

or stereoisomers or pharmaceutically acceptable salts thereof, wherein: Z is selected from O or S; R¹ and R² are independently selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl; R³ is a (CR^(3′)R^(3′))_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R¹⁵; R^(3′), at each occurrence, is independently selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl; R⁴ is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b), (CH₂)_(q)C(O)NR^(4a)R^(4a), (CH₂)_(q)C(O)OR^(4b), and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4c); R^(4a), at each occurrence, is independently selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl; R^(4b), at each occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and phenyl; R^(4c), at each occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4a)R^(4a), and (CH₂)_(r)phenyl; R⁵ is selected from

Y is selected from O, N(R²⁵), S, S(O), and S(O)₂; ring B is a 5-7 membered cycloalkyl ring optionally containing a C═O, and being substituted with 0-2 R^(11a), wherein the cycloalkyl ring is fused with a benzo group substituted with 0-3 R¹⁶ or is fused with a 5-6 membered aromatic heterocyclic ring having 0-3 N, 0-1 O, or 0-1 S, the heterocyclic ring being substituted with 0-3 R¹⁶; alternatively, ring B is a 5-7 membered saturated heterocyclic ring containing 0-1 O, N(R²⁵), S, S(O), and S(O)₂, substituted with 0-2 R^(11a), wherein the heterocyclic ring is fused with a benzo group substituted with 0-3 R¹⁶ or is fused with a 5-6 membered aromatic heterocyclic ring having 0-3 N, 0-1 O, or 0-1 S, the heterocyclic ring being substituted with 0-3 R¹⁶; provided that if ring B is a heterocyclic ring, then the number of carbon atoms separating the heteroatom of ring B and the nitrogen atom of formula (Ia) bonded to R⁵ is at least 2; R^(5a) is selected from a C₃₋₁₀ carbocyclic residue substituted with 0-5 R¹⁶, and a 5-10 membered heterocyclic residue containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁶; R⁶, at each occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(t)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃, CN, (CH₂)_(r)NR^(6a)R^(6a), (CH₂)_(r)OH, (CH₂)_(r)OR^(6b), (CH₂)_(r)SH, (CH₂)_(r)SR^(6b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a), (CH₂)_(r)NR^(6d)C(O)R^(6a), (CH₂)_(r)C(O)OR^(6b), (CH₂)_(r)OC(O)R^(6b), (CH₂)_(r)S(O)R^(6b), (CH₂)_(r)S(O)₂R^(6b), (CH₂)_(r)S(O)₂NR^(6a)R^(6a), (CH₂)_(r)NR^(6d)S(O)₂R^(6b), and (CH₂)_(t)phenyl substituted with 0-3 R^(6c); with the proviso that if R⁶ is attached to a carbon atom which also is attached to a nitrogen atom, or if two occurrences of R⁶ are attached to the same carbon atom, then r contained within the definition of such R⁶ must be greater than 0; R^(6a), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c); R^(6b), at each occurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c); R^(6c), at each occurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(6d)R^(6d); R^(6d), at each occurrence, is independently selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(11a) and R^(12a), at each occurrence, are independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(t)C₃₋₆ cycloalkyl, (CF₂)_(t)CF₃, (CH₂)_(r)N(R^(18a))R^(18b), (CH₂)_(r)OH, (CH₂)_(r)OR¹⁹, (CH₂)_(r)SH, (CH₂)_(r)SR¹⁹, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R¹⁹, (CH₂)_(r)C(O)N(R^(18a))R^(18b), (CH₂)_(r)N(R^(18c))C(O)R¹⁹, (CH₂)_(r)C(O)OR¹⁹, (CH₂)_(r)OC(O)R¹⁹, (CH₂)_(r)S(O)R¹⁹, (CH₂)_(r)S(O)₂R¹⁹, (CH₂)_(r)S(O)₂N(R^(18a))R^(18b), (CH₂)_(r)N(R^(18c))S(O)₂R¹⁹, and (CH₂)_(t)phenyl substituted with 0-3 R¹⁸; with the proviso that if s is 1, then r contained within the definition of such R^(11a) and R^(12a) attached to carbon atoms bonded directly to Y must be greater than 0; R^(11b), R^(12b), R^(14a) and R^(14b), at each occurrence, are independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃, (CH₂)_(q)N(R^(18a))R^(18b), (CH₂)_(q)OH, (CH₂)_(q)OR¹⁹, (CH₂)_(q)SH, (CH₂)_(q)SR¹⁹, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R¹⁹, (CH₂)_(r)C(O)N(R^(18a))R^(18b), (CH₂)_(q)N(R^(18c))C(O)R¹⁹, (CH₂)_(r)C(O)OR¹⁹, (CH₂)_(q)OC(O)R¹⁹, (CH₂)_(q)S(O)R¹⁹, (CH₂)_(q)S(O)₂R¹⁹, (CH₂)_(q)S(O)₂N(R^(18a))R^(18b), (CH₂)_(q)N(R^(18c))S(O)₂R¹⁹, and (CH₂)_(r)phenyl substituted with 0-3 R¹⁸; R¹⁵, at each occurrence, is independently selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN, (CHR′)_(r)NR^(15a)R^(15a), (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(15d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(15d), (CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(O)NR^(15a)R^(15a), (CHR′)_(r)NR^(15f)C(O)(CHR′)_(r)R^(15b), (CHR′)_(r)NR^(15f)C(O)NR^(15f)R^(15f), (CHR′)_(r)C(O)O(CHR′)_(r)R^(15d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(15b), (CHR′)_(r)C(═NR^(15f))NR^(15a)R^(15a), (CHR′)_(r)NHC(═NR^(15f))NR^(15f)R^(15f), (CHR′)_(r)S(O)(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂(CHR′)_(r)R^(15b), (CHR′)_(r)S(O)₂NR^(15a)R^(15a), (CHR′)_(r)NR^(15f)S(O)₂(CHR′)_(r)R^(15b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, (CHR′)_(r)phenyl substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e); R′, at each occurrence, is in dependently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(15e); R^(15a), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(15e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e); R^(15b), at each occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(15e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(15e); R^(15d), at each occurrence, is independently selected from C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(15e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(15e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(15e); R^(15e), at each occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(15f)R^(15f), and (CH₂)_(r)phenyl; R^(15f), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl; R¹⁶, at each occurrence, is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN, (CHR′)_(r)NR^(16a)R^(16a), (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(16d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(16d), (CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)NR^(16a)R^(16a), (CHR′)_(r)NR^(16f)C(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(O)O(CHR′)_(r)R^(16d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(16b), (CHR′)_(r)C(═NR^(16f))NR^(16a)R^(16a), (CHR′)_(r)NHC(═NR^(16f))NR^(16f)R^(16f), (CHR′)_(r)S(O)(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂(CHR′)_(r)R^(16b), (CHR′)_(r)S(O)₂NR^(16a)R^(16a), (CHR′)_(r)NR^(16f)S(O)₂(CHR′)_(r)R^(16b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and (CHR′)_(r)phenyl substituted with 0-3 R^(16e); R^(16a), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(16e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e); R^(16b), at each occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(16e); R^(16d), at each occurrence, is independently selected from C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(16e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(16e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(16e); R^(16e), at each occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(16f)R^(16f), and (CH₂)_(r)phenyl; R^(16f), at each occurrence, is independently selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R¹⁸, at each occurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)S(O)C₁₋₅ alkyl, (CH₂)_(r)S(O)₂C₁₋₅ alkyl, (CH₂)_(r)S(O)₂N(R^(18a))R^(18b), (CH₂)_(r)N(R^(18c))C(O)C₁₋₅ alkyl (CH₂)_(r)N(R^(18c))S(O)₂C₁₋₅ alkyl, (CH₂)_(r)C(O)N(R^(18a))R^(18b), (CH₂)_(r)C(O)OC₁₋₅ alkyl, (CH₂)_(r)C(O)C₁₋₅ alkyl, and (CH₂)_(r)N(R^(18a))R^(18b); R^(18a), R^(18b), and R^(18c), at each occurrence, are in dependently selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; alternatively, R^(18a) and R^(18b) along with the nitrogen to which both are attached form a pyrrolidine, piperidine, piperazine or morpholine ring; R¹⁹, at each occurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R¹⁸; R²⁵, at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(r)C(O)R¹⁹, (CH₂)_(r)C(O)N(R^(18a))R^(18b), (CH₂)_(r)C(O)OR¹⁹, (CH₂)_(r)S(O)₂R¹⁹, (CH₂)_(r)S(O)₂N(R^(18a))R^(18b), and (CH₂)_(r)phenyl substituted with 0-3 R¹⁸; a is selected from 0 and 1; b is selected from 0, 1, 2 and 3; with the proviso that a+b is selected from 1, 2 and 3; c is 1; d is 1; m is selected from 0, 1, and 2; s is selected from 0 and 1; with the proviso: m+s is selected from 0, 1, and 2; v is selected from 0, 1, 2, and 3; with the proviso: that the number of atoms in the shortest path linking the nitrogen to which R⁵ is attached and the fused benzo or aromatic heterocyclic ring of B contained within such R⁵ is less than or equal to 4; r is selected from 0, 1, 2, 3, 4, and 5; t is selected from 0, 1, 2, 3, 4, and 5; q is selected from 1, 2, 3, 4, and 5; and u is selected from 0, 1 and,
 2. 2. The compound of claim 1, wherein R¹ and R² are independently selected from H and C₁₋₈ alkyl; R⁴ is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4c); and R^(4c), at each occurrence, is independently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4a)R^(4a), and (CH₂)_(r)phenyl.
 3. The compound of claim 2, wherein Z is selected from O and S; R⁶, at each occurrence, is independently selected from C₁₋₄ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)NR^(6a)R^(6a), (CH₂)_(q)OH, (CH₂)_(q)OR^(6b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a), (CH₂)_(q)NR^(6d)C(O)R^(6a), (CH₂)_(r)S(O)₂NR^(6a)R^(6a), (CH₂)_(r)NR^(6d)S(O)₂R^(6b), and (CH₂)_(t)phenyl substituted with 0-3 R^(6c); R^(6a), at each occurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl, cyclohexyl, and phenyl; R^(6b), at each occurrence, is independently selected from methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl, cyclohexyl, and phenyl; R^(6c), at each occurrence, is independently selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(6d)R^(6d); and R^(6d), at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl, and cyclohexyl.
 4. The compound of claim 3, wherein R³ is selected from a (CR^(3′)H)_(r)—C₃₋₈ carbocyclic residue substituted with 0-5 R¹⁵, wherein the carbocyclic residue is selected from phenyl, and naphthyl; and R^(5a) is selected from phenyl substituted with 0-5 R¹⁶; and a heterocyclic residue substituted with 0-3 R¹⁶, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
 5. The compound of claim 4, wherein R¹ and R² are H; R^(5a) is phenyl substituted with 1-3 R¹⁶; R¹⁶, at each occurrence, is independently selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F, NR^(16a)R^(16a), NO₂, CN, OH, OR^(16d), C(O)R^(16b), C(O)NR^(16a)R^(16a), and NR^(16f)C(O)R^(16b); R^(16a), at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl, cyclohexyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16b), at each occurrence, is independently selected from methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl, cyclohexyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(16e); R^(16d), at each occurrence, is independently selected from methyl, ethyl, propyl, i-propyl, butyl, and phenyl; R^(16e), at each occurrence, is independently selected from methyl, ethyl, propyl, i-propyl, butyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and R^(16f), at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, and butyl.
 6. The compound of claim 1, wherein R⁴ is absent; R⁵ is

R^(11a) and R^(12a), at each occurrence, are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cylohexyl, CF₃, (CH₂)_(r)N(R^(18a))R^(18b), (CH₂)_(r)OH; R^(11b), R^(12b), R^(14a) and R^(14b), at each occurrence, are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cylohexyl, CF₃, (CH₂)_(q)N(R^(18a))R^(18b), (CH₂)_(q)OH; R²⁵, at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclopentyl, cyclohexyl, (CH₂)_(r)C(O)R¹⁹, (CH₂)_(r)C(O)N(R^(18a))R^(18b), (CH₂)_(r)C(O)OR¹⁹, and (CH₂)_(r)phenyl substituted with 0-3 R¹⁸.
 7. The compound of claim 6, wherein R⁵ is

R^(11a) and R^(12a), at each occurrence, are independently selected from H, methyl, ethyl and OH; R^(11b), R^(12b), R^(14a), and R^(14b), at each occurrence, are independently selected from H, methyl and ethyl; and R¹⁶, at each occurrence, is independently selected from methyl, Cl, F, CF₃, and CN.
 8. A compound of Table 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Table 1 is as follows: TABLE 1

Mass spec, Example A b c d R³ R⁵ (M + H)⁺ 1 0 1 1 1 3-ethyl-5-(1-methyl-tetrazol-5-yl)-C₆H₄ 4-F—C₆H₄—(CH₂)₂— 478 2 0 1 1 1 3-ethyl-5-(1-methyl-tetrazol-5-yl)-C₆H₄ 4-F—C₆H₄—(CH₂)₃— 
 492.


9. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim
 1. 10. A pharmaceutical composition comprised of a compound according to claim 1 and one or more active ingredients.
 11. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim
 8. 12. A pharmaceutical composition comprised of a compound according to claim 8 and one or more active ingredients. 